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Ayami Matsushima Last modified date:2023.04.09

Associate Professor / Organic and Biological Chemistry
Department of Chemistry
Faculty of Sciences

Graduate School
Undergraduate School

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Academic Degree
Ph. D
Country of degree conferring institution (Overseas)
Field of Specialization
Total Priod of education and research career in the foreign country
Research Interests
  • Studies on the mechanism in gene expression of nuclear receptors and the chemical risk assessments
    keyword : nuclear receptor, bisphenol A
  • The Study on nociceptin receptor antagonist
    keyword : nociceptin, antagonist, agonist
Academic Activities
1. 松島綾美, 解説 ビスフェノール類が環境ホルモンとして作用する機構を解明―コンピュータシミュレーションを駆使して見出した複雑な作用, 化学(化学同人)Vol. 77, No. 3, p 23-26 (2022), 2022.03.
2. Tagawa, K., Suyama, K., Kesamaru, H., Masuya, T., Nose, T., Matsushima, A., Design and synthesis of a universal coactivator peptide binding to the estrogen receptor and Nurr1., 2021.03.
1. Keitaro Suyama, Shuhei Kaneko, Hitoshi Kesamaru, Xiaohui Liu, Ayami Matsushima, Yoshimitsu Kakuta, Takashi Okubo, Kazumi Kasatani, Takeru Nose, Evaluation of the Influence of Halogenation on the Binding of Bisphenol A to the Estrogen-Related Receptor γ, Chemical Research in Toxicology, 10.1021/acs.chemrestox.9b00379, 33, 4, 889-902, 2020.04, Halogenation of organic compounds is one the most important transformations in chemical synthesis and is used for the production of various industrial products. A variety of halogenated bisphenol analogs have recently been developed and are used as alternatives to bisphenol A (BPA), which is a raw material of polycarbonate that has adverse effects in animals. However, limited information is available on the potential toxicity of the halogenated BPA analogs. In the present study, to assess the latent toxicity of halogenated BPA analogs, we evaluated the binding and transcriptional activities of halogenated BPA analogs to the estrogen-related receptor γ(ERRγ), a nuclear receptor that contributes to the growth of nerves and sexual glands. Fluorinated BPA analogs demonstrated strong ERRγbinding potency, and inverse antagonistic activity, similar to BPA. X-ray crystallography and fragment molecular orbital (FMO) calculation revealed that a fluorine-substituted BPA analog could interact with several amino acid residues of ERRγ-LBD, strengthening the binding affinity of the analogs. The ERRγbinding affinity and transcriptional activity of the halogenated BPAs decreased with the increase in the size and number of halogen atom(s). The IC50 values, determined by the competitive binding assay, correlated well with the binding energy obtained from the docking calculation, suggesting that the docking calculation could correctly estimate the ERRγbinding potency of the BPA analogs. These results confirmed that ERRγhas a ligand binding pocket that fits very well to BPA. Furthermore, this study showed that the binding affinity of the BPA analogs can be predicted by the docking calculation, indicating the importance of the calculation method in the risk assessment of halogenated compounds..
2. Hirofumi Ohga, Fumiko Akase, Ryo Sakanoue, Ayami Matsushima, Kohei Ohta, Michiya Matsuyama, Alanine scanning and characterization of core peptides in Scombridae fish family for construction of Kiss1 super analog, General and Comparative Endocrinology, 10.1016/j.ygcen.2019.113356, 288, 2020.03, Chronic Kiss1 administration strongly promotes gonadal development in immature chub mackerel (cm) (Scomber japonicus). Here, we performed an Alanine scanning (Ala-scanning) of Kiss1 to determine its key residues. Additionally, we examined functional peptides from 16 Scombridae species to develop maturation-inducing super-analogs that can be used universally in Scombridae species. In the Ala-scanning of Kiss1-15 (QDMSSYNFNSFGLRY), substitution of Gln1 and Asp2 did not affect agonistic activity. This suggests that peptides could be downsized. Furthermore, it is possible that Phe8 can be substituted by unnatural amino acids that are difficult to degrade. In molecular cloning, only Scomber showed a 16-residue form as a putative mature peptide. The other genera, did not have a His residue at the N-terminal, which indicated that the functional peptide was 15 residues and the second and third residues from the N-terminal showed variation between interspecies. Next, we examined the binding affinity of various synthetic Kiss1 core peptides in Scombridae interspecies using an SRE-Luc reporter system. We cloned Kiss1 receptors (KissR1) from bluefin tuna (bft) (Thunnus orientalis) and Japanese Spanish mackerel (jsm) (Scomberomorus niphonius) for the first time. In binding affinity with cmKissR1, bftKissR1, and jsmKissR1, the species specificity of the second residue from the N-terminus in each ligand could be ignored, but the difference in the third residue strongly affected receptor binding. Scombridae species possess the same Kiss1 system but the structure of the functional peptide might be species-specific..
3. Takahiro Masuya,Masaki Iwamoto, Xiaohui Liu, Ayami Matsushima, Discovery of novel oestrogen receptor α agonists and antagonists by screening a revisited privileged structure moiety for nuclear receptors, Scientific reports, 10.1038/s41598-019-46272-y, 9, 1, 2019.12, Bisphenol A (BPA) is used as an industrial raw material for polycarbonate plastics and epoxy resins; however, various concerns have been reported regarding its status as an endocrine-disrupting chemical. BPA interacts not only with oestrogen receptors (ERs) but constitutive androstane receptor, pregnane X receptor, and oestrogen-related receptor γ (ERRγ); therefore, the bisphenol structure represents a privileged structure for the nuclear-receptor superfamily. Here, we screen 127 BPA-related compounds by competitive-binding assay using [3H]oestradiol and find that 20 compounds bind to ERα with high affinity. We confirm most of these as ERα agonists; however, four compounds, including bisphenol M and bisphenol P act as novel antagonists. These structures harbour three benzene rings in tandem with terminal hydroxy groups at para-positions, with this tandem tri-ring bisphenol structure representing a novel privileged structure for an ERα antagonist. Additionally, we perform an ab initio calculation and develop a new clipping method for halogen bonding or non-covalent interaction using DV-Xα evaluation for biomolecules..
4. Xiaohui Liu, Hiroki Sakai, Mitsuhiro Nishigori, Keitaro Suyama, Tasuku Nawaji, Shin Ikeda, Makoto Nishigouchi, Hiroyuki Okada, Ayami Matsushima, Takeru Nose, Miki Shimohigashi, Yasuyuki Shimohigashi, Receptor-binding affinities of bisphenol A and its next-generation analogs for human nuclear receptors, Toxicology and Applied Pharmacology, 10.1016/j.taap.2019.114610, 377, 2019.08, An endocrine-disrupting chemical Bisphenol A (BPA) binds specifically to a nuclear receptor (NR) named ERRγ. Although the importance of receptor-binding evaluation for human NRs is often stressed, the binding characteristics of so-called next-generation (NextGen) bisphenol compounds are still poorly understood. The ultimate objective of this investigation was to evaluate BPA and its NextGen analogs for their abilities to bind to 21 human NRs, the greatest members of NRs for which tritium-labeled specific ligands were available. After establishing the detailed assay conditions for each NR, the receptor binding affinities of total 11 bisphenols were evaluated in competitive binding assays. The results clearly revealed that BPA and the NextGen bisphenols of BPAF, BPAP, BPB, BPC, BPE, and BPZ were highly potent against one or more of NRs such as CAR, ERα, ERβ, ERRγ, and GR, with IC50 values of 3.3–73 nM. These bisphenols were suggested strongly to be disruptive to these NRs. BPM and BPP also appeared to be disruptive, but less potently. BPF exhibited only weak effects and only against estrogen-related NRs. Surprisingly, most doubtful bisphenol BPS was supposed not to be disruptive. The NRs to which BPA and NextGen bisphenols did not bind were RARα, RARβ, RARγ, and VDR. PPARγ, RORα, RORβ, RORγ, RXRα, RXRβ, and RXRγ, exhibited very weak interaction with these bisphenols. The ten remaining NRs, namely, ERRγ, ERβ, ERα, CAR, GR, PXR, PR, AR, LXRβ, and LXRα, showed distinctly strong binding to some bisphenols in this order, being likely to have consequential endocrine-disruption effects..
5. Ayami Matsushima, Jun Sese, Kanako O. Koyanagi, Biosynthetic Short Neuropeptides
A Rational Theory Based on Experimental Results for the Missing Pain-Relief Opioid Endomorphin Precursor Gene, ChemBioChem, 10.1002/cbic.201900317, 20, 16, 2054-2058, 2019.01, Endomorphins are neuropeptides that bind strongly to μ-opioid receptors and are considered to play important roles in pain modulation and other biological functions. Two endomorphins have been identified, to date, endomorphine-1 and -2; both are tetrapeptides and differ by only a single amino acid in the third position. Both peptides were isolated from bovine brains; however, their precursor genes have not been identified. In this study, a nucleotide sequence corresponding to the endomorphin-1 peptide in an expressed sequence tag database has been found and a preproendomorphin-like precursor peptide from human brain complementary DNA (cDNA) has been cloned. The cDNA consists of nucleotide sequences of two already annotated predicted genes, and the putative peptide differs by one amino acid from the isolated endomorphin peptides. It is proposed herein that there is the possibility of unknown short proteins or peptide precursors being missed by automated gene prediction programs based on similarities of known protein sequences. A novel concept of how to produce endomorphins from a similar peptide is described. The oxidatively modified base might provide a clue for understanding discrepancies between nucleotide sequences on the genome and those on cDNAs..
6. Matsushima, A., A Novel Action of Endocrine-Disrupting Chemicals on Wildlife; DDT and Its Derivatives Have Remained in the Environment, Int. J. Mol. Sci., DOI:10.3390/ijms19051377, 19, 5, e1377, 2018.04.
7. Matsushima, A., Nishiimura, H., Matsuyama, Y., Liu, X., and Shimohigashi. Y., Docking simulation to elucidate the labeled cysteine residue of the nociception receptor ORL1 using a Cys(Npys)-containing peptide ligand, Peptide Science 2016, 88, 2017.03.
8. Ayami Matsushima, Hiroyuki Nishimura, Yutaka Matsuyama, LIU XIAOHUI, Tomasso Costa, Yasuyuki Shimohigashi, Specific affinity-labeling of the nociceptin ORL1 receptor using a thiol-activated Cys(Npys)-containing peptide ligands, Biopolymers Peptide Science, 10.1002/bip.22792., 2016.03.
9. 劉 暁輝、松島綾美、下東康幸, 乳がん細胞における内分泌撹乱物質ビスフェノールのエストロゲン受容体応答, 月刊 細胞 the cell(ニューサイエンス), 2016.03.
10. LIU XIAOHUI, Ayami Matsushima, Miki Shimohigashi, Yasuyuki Shimohigashi, A characteristic back support structure in the bisphenol A-binding pocket in the human nuclear receptor ERR, PLoS ONE, 10.1371/journal.pone.0101252, 9, e101252, 2014.06.
11. Jinglan Li, Hirokazu Nishimura, Ayami Matsushima, Yasuyuki Shimohigashi, N-Methylthioacetylation of RYYRIK-NH2 with enhanced specific binding affinity and high antagonist activity for nociceptin ORL1 receptor, Bioorg. Med. Chem., 10.1016/j.bmc.2014.09.049, 22, 5712-5716, 2014.05.
12. Shogo Inamine, Hirokazu Nishimura, Jinglan Li, Kaname Isozaki, Ayami Matsushima, Tomasso Costa, Yasuyuki Shimohigashi, Tritium-labelled isovaleryl-RYYRIK-NH2 as potential antagonist probe for ORL1 nociceptin receptor, Bioorg. Med. Chem., 10.1016/j.bmc.2014.09.049, 22, 5902-5909, 2014.05.
13. LIU XIAOHUI, Akina Fujiyama, Ayami Matsushima, Miki Shimohigashi, Yasuyuki Shimohigashi, α-Helix-Peptides Composing the human nuclear receptor ERRγ competitively provoke inhibition of functional homomeric dimerization., Biopolymers Peptide Science, 10.1002/bip.22795., 2014.03.
14. Ayami Matsushima, Hirokazu Nishimura, Shogo Inamine, Yasuyuki Shimohigashi, Identification of affinity binding site of Cys(Npys)-elongated RYYRIK peptide antagonist by means of Cys→Ala mutated ORL1 nociceptin receptors., Peptide Science 2012, 115-118, 2013.03, We have previously developed a peptidic affinity ligand for the ORL1 nociceptin receptor. It contains Cys(Npys) instead of isovareroyl of a pure antagonist peptide isovareroyl-RYYRIK-NH2. In this study, in order to identify the exact binding site of Cys(Npys), we performed affinity labeling experiments of a series of Cys→Ala mutated ORL1 receptors. A certain number of mutant receptors showed labeling effectiveness weaker than wild type receptor, suggesting that the recepor Cys was labeled by Cys(Npys)-RYYRIK-NH2..
15. Ayami Matsushima, Kerrianne Ryan, Yasuyuki Shimohigashi, Ian A. Meinertzhagen, An endocrine disruptor, bisphenol A, affects development in the protochordate Ciona intestinalis, Environ. Pollut., 10.1016/j.envpol.2012.10.015, 173, 257-263, 2013.02.
16. Liu X, Matsushima A, Nakamura M, Costa T, Nose T, Shimohigashi Y, Fine spatial assembly for construction of the phenol-binding pocket to capture bisphenol A in the human nuclear receptor estrogen-related receptor γ., J. Biochem. , 10.1093/jb/mvs008, 151, 4, 403-415, 2012.04, Various lines of evidence have shown that bisphenol A (BPA) acts as an endocrine disruptor that affects various hormones even at merely physiological levels. We demonstrated recently that BPA binds strongly to human nuclear receptor estrogen-related receptor γ (ERRγ), one of 48 nuclear receptors. Based on X-ray crystal analysis of the ERRγ ligand-binding domain (LBD)/BPA complex, we demonstrated that ERRγ receptor residues, Glu275 and Arg316, function as the intrinsic-binding site of the phenol-hydroxyl group of BPA. If these phenol-hydroxyl↔Glu275 and Arg316 hydrogen bonds anchor the A-benzene ring of BPA, the benzene-phenyl group of BPA would be in a pocket constructed by specific amino acid side chain structures. In the present study, by evaluating the Ala-replaced mutant receptors, we identified such a ligand-binding pocket. Leu268, Leu271, Leu309 and Tyr326, in addition to the previously reported participants Glu275 and Arg316, were found to make a receptacle pocket for the A-ring, whereas Ile279, Ile310 and Val313 were found to assist or structurally support these residues. The results revealed that each amino acid residue is an essential structural element for the strong binding of BPA to ERRγ..
17. Matsushima, A., Nishimura, H., Inamine, S., Uemura, S., Shimohigashi, Y., Capturing of the free cysteine residue in the ligand-binding site by affinity labeling of the ORL1 nociceptin receptor., Bioorg. Med. Chem., 10.1016/j.bmc.2011.10.024 , 19, 7597–7602, 2011.09, All of the δ, μ, and κ opioid receptors have a free thiol group of the Cys residue in the ligand-binding site, although its functional role is not yet known. In order to examine whether or not a similar Cys is also present in the ORL1 nociceptin receptor, we attempted to identify it by affinity labeling using a specific antagonist peptide. We first treated ORL1-expressing COS-7 cell membrane preparations with the thiol-alkylation reagent N-ethylmaleimide (NEM) to perform a binding assay using [(3)H]nociceptin as a tracer and nociceptin, an ORL1 agonist, or Ac-Arg-Tyr-Tyr-Arg-Ile-Lys-NH(2), a nociceptin/ORL1 antagonist, as a competitor. It was suggested that ORL1 has a free Cys in its ligand-binding site, since the NEM treatment reduced the population of ligand-binding sites. This was further confirmed by affinity labeling using Cys(Npys)-Arg-Tyr-Tyr-Arg-Ile-Lys-NH(2) with the SNpys group that can react with a free thiol group, resulting in the formation of a disulfide bond. This affinity labeling was approximately 23 times more specific than NEM alkylation. The results revealed that the ORL1 nociceptin receptor does contain a free Cys residue in the ligand-binding site..
18. Liu, X., Matsushima, A., Okada, H., and Shimohigashi, Y., Distinction of the binding modes for human nuclear receptor ERRγ between bisphenol A and 4-hydroxytamoxifen, J. Biochem, 148, 247–254, 2010.05.
19. Matsushima, A., Liu, X., Okada, H., Shimohigashi, M., and Shimohigashi, Y, Bisphenol AF is a Full Agonist for the Estrogen Receptor ERα, but a Highly Specific Antagonist for ERβ., Environ. Health Perspect., 2010.04.
20. Li, J., Isozaki, K., Matsushima, A., Nose, T., Costa, T., and Shimoohigashi, Y., Structure-function analysis of nociceptin receptor ORL1 by the site-directed mutagenesis, Peptide Science 2009, 219–220, 2010.03.
21. Sato, K., Horiuchi, Y., Matsushima, A., and shimohigashi, Y., The preparation and purification of prion protein N-terminal domain with fluctuations in the number of octapeptide repeat, Peptide Science 2009, 433–434 , 2010.03.
22. Liu, X., Matsushima, A., Okada, H., and Shimohigashi, Y., Functional role of the C-terminal Helix 12 peptide in the receptor activation mechanism of estrogen-related receptor γ (ERRγ)., Peptide Science 2009, 435–436, 2010.03.
23. Takeda, Y., Liu, X., Sumiyoshi, M., Matsushima, A., Shimohigashi, M., and Shimohigashi, Y., Placenta expressing the greatest quantity of bisphenol A receptor ERRγ among the human reproductive tissues: predominant expression of type-1 ERRγ isoform, J. Biochem., , 146, 113-122, 2009.10.
24. Matsushima, A., Okada, H., Liu, X., Tokunaga, T., Teramoto, T., Kakuta, Y., Shimohigashi, Y., Induced-fit type ligand binding guided by free-rotatory Leu residue present in the 7th α-helix peptide in the estrogen-related receptor γ (ERRγ), Peptide Science 2008, 521-522, 2009.03.
25. Matsushima. A., Teramoto, T., Okada, H., Liu, X., Tokunaga, T., Kakuta, Y., and Shimohigashi, Y., ERRγ tethers strongly bisphenol A and 4-α-cumylphenol in an induced-fit manner., Biochem. Biophys. Res. Commun., 373, 408-413 (2008), 2008.12.
26. Yokotani, S., Nose, T., Horiuchi, Y., Matsushima, A., and Shimohigashi, Y., Radar chart deviation analysis of prion protein amino acid composition defines characteristic structural abnormalities of the N-terminal octapeptide tandem repeat., Protein Peptide Sci., 15, 949-955 (2008), 2008.08.
27. Okada, H., Tokunaga, T., Lui, X., Takayanagi, S., Matsushima, A., and Shimohigashi, Y., Direct evidence revealing structural elements essential for the high binding ability of bisphenol A to human estrogen-related receptor γ (ERRγ)., Environ. Health Perspect., 116, 32-38 (2008), 2008.01.
28. Li, J. Isozaki, K., Okada, K., Matsushima, A., Nose, T., Costa, T., and Shimohigashi, Y., Design Synthesis of Highly Potent Antagonist of ORL1 Nociceptin Receptor., Bioorg. Med. Chem., 16, 2635-2664 (2008), 2008.01.
29. Li, J. Isozaki, K., Matsushima, A., Nose, T., Costa, T., and Shimohigashi, Y., Optimization of the N-Terminal Group of Ac-RYYRIK-NH2 as ORL1 Receptor Antagonist, Peptide Science 2007, 257-260 (2008), 2008.01.
30. Takeda, Y., Koga, K., Matsushima, A., Shimohigashi, M., and Shimohigashi, Y., The Output Mechanism of Circadian Pacemaker Neuropeptide PDF in the Regulation of Bimodal Locomotor Distribution, Peptide Science 2007, 65-68 (2008), 2008.01.
31. Matsushima, A., Koretsune, Y., Kaneki, A., Isozaki, K., Shimohigashi, M., and Shimohigashi, Y., Structural Requirement of Housefly FMRFamide Peptides in Its Receptor Activation., Peptide Science 2007, 313-314 (2008), 2008.01.
32. Hattori, E., Yokotani, S., Horiuchi, Y., Matsushima, A., and Shimohigashi, Y., The Effect of Amino Acid Substitution on Oligomerization of Octapeptide Repeat Structure in Prion Protein. , Peptide Science 2007, 239-242 (2008), 2008.01.
33. Matsushima, A., Kakuta, Y., Teramoto, T., Koshiba, T., Liu, X., Okada, H., Tokunaga, T., Kawabata, S., Kimura, M., and Shimohigashi, Y., Structural Evidence for Endocrine Disruptor Bisphenol A Binding to Human Nuclear Receptor ERRγ, J. Biochem., 142, 517-524 (2007), 2007.10.
34. Liu, X., Matsushima, A., Okada, H., Tokunaga, T., Isozaki, K., and Shimohigashi, Y., Receptor binding characteristics of endocrine disruptor bisphenol A: Chief and corroborative hydrogen bonds of bisphenol A phenol-hydroxyl group with Arg316 and Glu275 residues in the human nuclear receptor of estrogen-related receptor γ , FEBS J., 274, 6340-6351 (2007), 2007.10.
35. Matsushima, A., Takano, K., Yoshida, T., Takeda, Y., Yokotani, S., Shimohigashi, Y., and Shimohigashi, M., Double-labeled in situ Hybridization Reveals the Lack of Co-localization of mRNAs for the Circadian Neuropeptide PDF and FMRFamide in Brains of the Flies Musca domestica and Drosophila melanogaster, J. Biochem, 141, 867-877 (2007), 2007.06.
36. Matsushima, A. Koretsune, Y., Kaneki, A. Isozaki, K., Shimohigashi, M., and Shimohigashi, Y., Structure-Activity Studies of FMRFamide-Related Peptides in Activating the Specific Receptor Present in the Housefly Musca domestica, Peptide Science 2006, 174, (2006), 2006.12.
37. Takayanagi, S., Tokunaga, T., Liu, X., Okada, H., Matsushima, A., and Shimohigashi, Y., Endocrine disruptor bisphenol A strongly binds to human estrogen-related receptor γ (ERRγ) with high cinstitutive activity, Toxicol. Lett., 195, 95-105 , 2006.11.
38. Matsushima, A., Horiuchi, Y., Yokotani, S., Kawano, M., and Shimohigashi, Y., Specific dimerization of prion protein N-terminal domain, Peptide Science 2005, 457-458 (2006), 2006.03.
39. Sato, S., Jonathan C., Corrins, Takeda, Y., Kaneki, A., Matsushima, A., Shimohigashi, Y., and Shimohigashi, M., Identification of novel isoforms of the circadian neuropeptide PDF in the silk moth Bombyx mori and their expression in brain, Peptide Science 2005, 99-100 (2006), 2006.03.
40. Horiuchi, Y., Kawano, M., Yokotani, S., Honda, T., Matsushima, A., Nose, T., and Shimohigashi, Y., Structural Characteristics of the N-Terminal Octapeptide Repeat Region of Prion Protein in Self-Polymerization, Peptide Science 2004, 317-318 (2005), 2005.03.
41. okotani, S., Matsushima, A., Nose, T., Morishita, F., and Shimohigashi Y., Bioactive Conformation of a D-Trp-Containing Cardioexcitatory Tripeptide Isolated from the Sea Hare Aplysia, Peptide Science 2004, 539-540 (2005), 2005.03.
42. Sato, S., Sumida, K., Hiramura, D., Matsushima, A., Tominaga, Y., Shimohigashi, Y., and Shimohigashi, M., cDNA Cloning and mRNA Expression of the Circadian Neuropeptide PDF in the Silk Moth Bombyx mori, Peptide Science 2004, 197-200 (2005), 2005.03.
43. Liu, X., Matsushima, A., Shirasu, N., Tominaga, Y., Shimohigashi, M., Shimohigashi, Y., and Nose, T., Structural Characteristics of Drosophila Estrogen-Related Receptor Ligand Binding Domain to Capture the Peptide and Non-peptide Ligands, Peptide Science 2004, 303-304 (2005), 2005.03.
44. Matsushima, S., Yokotani, S., Sato, S., Kaneki, A., Takeda, Y., Chuman, Y., Ozaki, M., Asai, D., Nose, T., Onoue, H., Ito, Y., Tominaga, Y., Shimohigashi, Y., and Shimohigashi, M., Molecular Cloning and Circadian Expression Profile of Pacemaker Neuropeptide PDF in Diptera, Lett., Peptide Sci., 10, 419-430 (2003), 2005.01.
45. Matsushima ., Yokotani, S., Koretsune, Y., Meinertzhagen, I.A., Tominaga, Y., Shimohigashi, M., and Shimohigashi, Y., FMRFamide-Related Peptides in the Nervous System of the Housefly Musca domestica: cDNA Cloning and Actions on Clam Heart Contraction, Peptide Science 2004, 157-160 (2005)., 2005.01.
46. Soto, S., Chuman, Y., Matsushima, A., Tominaga, K., Shimohigashi, Y., and Shimohigashi, M., A Circadian Neuropeptide, Pigment-Dispersing Factor-PDF, in the Last-Summer Cicada Meimuna opalifera: cDNA Cloning and Immunocytochemistry, Zool. Sci., 10.2108/zsj.19.821, 19, 8, 821-828, 19, 821-828, 2002.12.
47. Chuman, Y., Matsushima, A., Sato, S., Tomioka, K., Tominaga, Y., Meinertzhagen, I.A., Shimohigashi, Y., and Shimohigashi, M., cDNA Cloning and Nuclear Localization of the Circadian Neuropeptide Designated as Pigment-Dispersing Factor PDF in the Cricket Gryllus bimaculatus, J., Biochem., 131, 6, 895-903, 131, 895-903, 2002.11.
48. Matsushima, A., Chuman, Y., Sato, S., Tominaga, Y., Shimohigashi, Y., and Shimohigashi M., Structure and Function of Nuclear Localization Signal Peptide Present in Circadian Rhythm Hormone Peptide Precursor, Comp. Biochem. Physiol., 127, 374, 2002.03.
49. Sato, S., Matsushima, A., Chuman, Y., Tominaga, K., Shimohigashi, Y., and Shimohigashi, M., cDNA Cloning of PDF Peptide Precursors in Housefly and Last Summer Cicada, Peptide Science 2001, 139-142, 2002.03.
50. Tokunaga, T., Ohtani, M., Matsushima, A., Chuman, Y., Nose, T., Shimohigashi, Y., Aimoto, S., and Shimohigashi, Y., Contractile Activity of Drosophila FMRFamide-Related Peptides in the Meretrix Lusoria Heart Muscle, Peptide Science 2001, 167-170 , 2002.03.
51. Asai, D., Tokunaga, T., Matsushima, A., Sato, S., Chuman, Y., Nose, T., Tominaga, Y., Shimohigashi, Y., and Shiimohigashi, M., Design and Preparation of Universal Anti-PERIOD Antibodies and their Immunoresponses, Peptide Science 2001, 399-402, 2002.03.
52. Matsushima, A., Chuman, Y., Onoue, H., Ito, Y., Tomioka, K., Tominaga, Y., Shimohigashi, Y., and Shimohigashi M., Gene Expression of a Circadian Pacemaker Hormone Peptide PDF in Cricket Gryllus bimaculatus,, Peptide Science 2000, 63-66, 2001.03.
53. Chuman, A., Matsushima, T., Nose, Y., Shimohigashi, and M., Shimohigashi, cDNA Cloning of Circadian Rhythm Pacemaker Neuropeptide PDF in Gryllus bimaculatus and Its Neuclear Localization, Peptide Science 2000, 59-62, 2001.03.
54. Fujita, T., Inoue, N., Matsuhima, A., Nose, T., Costa, T., and Shimohigashi, Y., Activity Enhancement by Introduction of Two Different Halogen Atoms into Phe-2-phenyl Group of Thrombin Receptor Tetherd-Ligand Analogs, Peptide Science 2000, 135-138, 2001.03.
55. Matsushima, A., Cuman, Y., Sato, S., Shimohigashi, Y., Tominaga, Y., and Shimohigashi, M., cDNA cloning of a Circadian Rhythm Pacemaker Hormone PDF of theHouse Fly Musca domestica, Comp. Biochem. Physiol., 130, 876, 2001.02.
56. Sato, S., Chuman, Y., Matsushima, A., Shimohigashi, Y., Tominaga, Y., and Shimohigashi, M., PERIOD Clock Protein of the Summer Cicada Meimuna opalifera: cDNA Cloning and Structural Analysis, Comp. Biochem. Physiol., 130, 874, 2001.02.
57. Matsushima, A., Fujita, T., Okada, K., Yamauchi, Y., Nose, T., and Shimohigashi, Y., Chemical Syntheses of Phenylalanine Derivatives Containing Halogenated Benzene Ring as Structural Explorers for Elucidation of Molecular Mechanisms of Receptor Interactions, Peptide Science 1999, 141-142, 2000.03.
58. Matsushima, A., Fujita, T., Okada, K., Shirasu, N., Nose, T., and Shimohigashi, Y., Exploration of the Role of Phenylalanine in the Thrombin Rwcwptor Tethered-Ligand Peptide by Substitution with a Series of Trifluorophenylalanines, Bull. Chem. Soc. Jpn, 10.1246/bcsj.73.2531, 73, 11, 2531-2538, 73, 2531-2538 , 2000.02.
59. Matsushima, A., Fujita, T., Okada, K., Nose, T., and Shimohigashi, Y., Edge-to-face CH/π Interaction between Ligand Phe-phenyl and Receptor Aromatic Group in Thrombin Receptor Activation, J. Biochem., 128, 2, 225-232, 128, 225-232, 2000.02.
60. Fujita, T., Nose, T., Matsushima, A., Okada, K., Asai, D., Yamauchi, Y., Shirasu, N., Honda, T., Shigehiro, D., and Shimohigashi, Y., Synthesis of complete set of L-difluorophenylalanines, L-(F2)Phe, as molecular explorers for the CH/π interaction between peptide ligand and receptor , Tetrahedron Letters, 41, 923-927 , 2000.02.
61. Fujita,T., Nose, T., Matsushima, A., Costa, T., and Shimohigashi, Y., Importance of Ligand Phe-phenyl Group for Activation of Thrombin Receptor, Peptide Science 1998, 33-36, 1999.03.
1. @Ayami Matsushima, Halogen-containing Environmental Chemicals Bind to Nuclear Receptors, he 19th Malaysian International Chemistry Congress & International Congress on Pure & Applied Chemistry Langkawi 2018, 2018.10, Environmental chemicals, such as pesticides and raw materials of resins, have the potential to induce adverse effects to wildlife and humans. Most of unfavorable effects derive from signal transduction via activated receptors, which is transmitted by simple ligand-receptor interactions. These receptor-mediated adverse effects are recognized as signal tocxicity, and the chemicals are called endocrine-disrupting chemicals (EDCs). Ligand-receptor interactions are constructed by weak interactions such as electrostatic and hydrophobic interactions, however, the detail mechanism of hydrophobic interactions in biomolecules is still obscure. There are many kinds of receptors, for instance, nuclear receptors in nuclei and membrane receptors on the cell membrane. In this paper, we present structure-activity studies on nuclear receptors and EDCs which are released into the environment. We have a strong interest in -interactions composed of aromatic amino acid residues. The crystal structures of ligands bound to nuclear receptors are also illustrated. We also evaluated the stability of ligand/receptor complexes using some computer calculations. Halogen-containing ligands will also be a useful tool to control receptor-ligand interactions by constructing halogen bonds between receptors and their ligands..
2. 松島綾美, 環境ホルモン学会に参加して10年:10年間の核内受容体とリガンドの構造活性相関解析研究, 第19回環境ホルモン学会研究発表会, 2016.12.
3. 松島綾美, 核内受容体とハロゲン含有環境化学物質の精緻な構造活性相関, DV-Xα研究協会, 2016.12.
4. 松島 綾美, 西村裕一, 劉 暁輝, 武末祐貴, 松山祐昂, 下東 康幸, Comprehensive structural analysis of the nociceptin ORL1 receptor by means of virtual and experimental Ala-scanning combined methods, 第52回ペプチド討論会, 2015.11.
5. 劉 暁輝, 下東美樹, 松島 綾美, 下東 康幸, Protein constitutive peptide fragments to inhibit protein-protein interaction: Inhibitory peptides as molecular probe for clarification of human nuclear receptor activation mechanism, 第52回ペプチド討論会, 2015.11.
6. Ayami Matsushima, H. Nishimura, S. Inamine, 下東 康幸, Multiple and Simultaneous Cys→Ala Mutations of ORL1 Nociceptin Receptor to Identify the Affinity Binding site of Cys(Npys)-Elongated RYYRIK Peptide Antagonist., The 4th Asia-Pacific International Peptide Symposium / The 50th Japanese Peptide Symposium, 2013.11.
7. LIU XIAOHUI, A. Fujiyama, H. Nishimura, Ayami Matsushima, 下東 康幸, Constitutive α-Helix-peptides Required for Functional Dimerization of Estrogen-related Receptor γ (ERRγ), The 4th Asia-Pacific International Peptide Symposium / The 50th Japanese Peptide Symposium, 2013.11.
8. Ayami Matsushima, Structure activity relationships between nuclear receptors and newly developed bisphenol A derivatives, NIEHS Seminar, 2013.07.
9. Ayami Matsushima, Structure activity relationships between nuclear receptors and novel Bisphenol A derivative, "Crossing Boundaries with Informatics -from Basic Science to Social Infrastructure": US-Japan "Connections" Symposium for Women Leaders in Science, Technology and Engineering and Mathematics, 2013.07.
10. Exploration of high-affinity chemicals for nuclear receptors and their possible endocrine-disrupting effects as “inverse antagonists” .
11. Exploration of high-affinity chemicals for nuclear receptors and their possible endocrine-disrupting effects as “inverse antagonists” .
12. 松島 綾美, 下東 康幸, Extraordinary Strong Binding of Human Nuclear Receptor ERRγ with Endocrine-Disrupting Chemical BisphenolA, 第16回韓国ペプチド・タンパク質シンポジウム, 2012.11.
13. Exploration of high-affinity chemicals for nuclear receptors and their possible endocrine-disrupting effects as “inverse antagonists” .
14. Multiple Post-transcriptional Regulations in Circadian Pacemaker Neuropeptide pdf Gene.
15. Conformation Change of α-Helix Peptide for Sensing of Deactivation of Nuclear Receptor: Immunoassay Using Polyclonal Antibody Specific for the C-terminal -Helix 12 of Estrogen-related Receptor γ (ERRγ).
16. Structure-Activity Studies of FMRFamide-Related Peptides in Activating the Specific Receptor Present in the Housefly Musca domestica.
  • Elucidation of molecular mechanism of receptor activation using fluorine-containing aromatic ligands
  • Structure-function studies between the hormone-disrupting chemical bisphenols and the nuclear receptors