본문 바로가기
KERD
논문KCI 등재

Molecular docking study on the α3β2 neuronal nicotinic acetylcholine receptor complexed with α-Conotoxin GIC

김도형|한규훈|이제욱|Si-Hyung Lee
생화학분자생물학회 (Korean Society Of Biochemistry And Molecular Biology)|2012.05|BMB Reports|제45권 제5호|pp. 275-280|DOI http://dx.doi.org/

1

조회

0

다운로드

0

인용

0

참고문헌

키워드

Homology modelingα-Conotoxin GICLigand-dockingMolecular dynamics (MD) simulationsNicotinic acetylcholine receptors (nAChRs)
주제분류화학

초록

Nicotinic acetylcholine receptors (nAChRs) are a diverse family of homo- or heteropentameric ligand-gated ion channels. Understanding the physiological role of each nAChR subtype and the key residues responsible for normal and pathological states is important. α-Conotoxin neuropeptides are highly selective probes capable of discriminating different subtypes of nAChRs. In this study, we performed homology modeling to generate the neuronal α3, β2 and β4 subunits using the x-ray structure of the α1 subunit as a template. The structures of the extracellular domains containing ligand binding sites in the α3β2 and α3β4 nAChR subtypes were constructed using MD simulations and ligand docking processes in their free and ligand-bound states using α-conotoxin GIC, which exhibited the highest α3β2 vs. α3β4 discrimination ratio. The results provide a reasonable structural basis for such a discriminatory ability, supporting the idea that the present strategy can be used for future investigations on nAChR-ligand complexes. [BMB reports 2012; 45(5): 275-280]

Abstract

Nicotinic acetylcholine receptors (nAChRs) are a diverse family of homo- or heteropentameric ligand-gated ion channels. Understanding the physiological role of each nAChR subtype and the key residues responsible for normal and pathological states is important. α-Conotoxin neuropeptides are highly selective probes capable of discriminating different subtypes of nAChRs. In this study, we performed homology modeling to generate the neuronal α3, β2 and β4 subunits using the x-ray structure of the α1 subunit as a template. The structures of the extracellular domains containing ligand binding sites in the α3β2 and α3β4 nAChR subtypes were constructed using MD simulations and ligand docking processes in their free and ligand-bound states using α-conotoxin GIC, which exhibited the highest α3β2 vs. α3β4 discrimination ratio. The results provide a reasonable structural basis for such a discriminatory ability, supporting the idea that the present strategy can be used for future investigations on nAChR-ligand complexes. [BMB reports 2012; 45(5): 275-280]

참고문헌 (41)

  1. Corringer, P. J., "Nicotinic receptors at the amino acid level", Annu. Rev. Pharmacol. Toxicol., 40, pp.431~458 (2000)
  2. Arias, H. R., "Localization of agonist and competitive antagonist binding sites on nicotinic acetylcholine receptors", Neurochem. Int., 36, pp.595~645 (2000)
  3. Paterson, D., "Neuronal nicotinic receptors in the human brain", Prog. Neurobiol., 61, pp.75~111 (2000)
  4. Myers, R. A., "Conus peptides as chemical probes for receptors and ion channels", Chem. Rev., 93, pp.1923~1936 (1993)
  5. Hu, S. -H., "Crystal structure at 1.1 Å resolution of α-conotoxin PnIB: Comparison with α-conotoxins PnIA and GI", Biochemistry, 36, pp.11323~11330 (1997)
  6. McIntosh, J. M., "α-Conotoxin GIC from Conus geographus, a novel peptide antagonist of nicotinic acetylcholine receptors", J. Biol. Chem., 277, pp.33610~33615 (2002)
  7. Martinez, J. S., "α-Conotoxin EI, A new nicotinic acetylcholine receptor antagonist with novel selectivity", Biochemistry, 34, pp.14519~14526 (1995)
  8. López-Vera, E., "Novel α-conotoxins from Conus spurius and the α-conotoxin EI share high-affinity potentiation and low-affinity inhibition of nicotinic acetylcholine receptors", FEBS J., 274, pp.3972~3985 (2007)
  9. McIntosh, J. M., "A novel α-conotoxin, PeIA, cloned from Conus pergrandis, discriminates between rat α9α10 and α7 nicotinic cholinergic receptors", J. Biol. Chem., 280, pp.30107~30112 (2005)
  10. López-Vera, E., "A novel alpha conotoxin (α-PIB) isolated from C. purpurascens is selective for skeletal muscle nicotinic acetylcholine receptors", Toxicon, 49, pp.1193~1199 (2007)
  11. Sandall, D. W., "A novel α-conotoxin Identified by gene sequencing is active in suppressing the vascular response to selective stimulation of sensory nerves in vivo", Biochemistry, 42, pp.6904~6911 (2003)
  12. Cartier, G. E., "A new α-conotoxin which targets 32 nicotinic acetylcholine receptors", J. Biol. Chem., 271, pp.7522~7528 (1996)
  13. Gray, W. R., "Peptide toxins from Conus geographus venom", J. Biol. Chem., 256, pp.4734~4740 (1981)
  14. Chi, S. -W., "Solution conformation of alpha-conotoxin GIC, a novel potent antagonist of alpha 3 beta 2 nicotinic acetylcholine receptors", BIOCHEMICAL JOURNAL, 380, pp.347~352 (2004), PORTLAND PRESS LTD
  15. Chi, S. -W., "Solution structure of α-conotoxin PIA, a novel antagonist of α6 subunit containing nicotinic acetylcholine receptors", Biochem. Biophys. Res. Commun., 338, pp.1990~1997 (2005)
  16. Chi, S. -W., "Solution conformation of αA-conotoxin EIVA, a potent neuromuscular nicotinic acetylcholine receptor antagonist from Conus ermineus", J. Biol. Chem., 278, pp.42208~42213 (2003)
  17. αA-conotoxin PIVA, "Biochemistry", 1997, 1669~1677
  18. EpI, a novel α-conotoxin from Conus episcopatus, solved by direct methods, "Biochemistry", 1998, 11425~11433
  19. Park, K. -H., "Solution conformation of α-conotoxin EI, a neuromuscular toxin specific for the α1", δ subunit interface of torpedo nicotinic acetylcholine receptor, 2001, pp.276, 49028~49033
  20. Shon, K. -J., "Three-dimensional solution structure of α-conotoxin MII, an α3β2 neuronal nicotinic acetylcholine receptor- targeted ligand", Biochemistry, 36, pp.15693~15700 (1997)
  21. Cho, J. -H., "Nuclear magnetic resonance solution conformation of α-conotoxin AuIB, an α3β4 subtype- selective neuronal nicotinic acetylcholine receptor antagonist", J. Biol. Chem., 275, pp.8680~8685 (2000)
  22. Brejc, K., "Crystal structure of an ACh-binding protein reveals the ligand-binding domain of nicotinic receptors", Nature, 411, pp.269~276 (2001)
  23. Celie, P. H. N., "Crystal structure of nicotinic acetylcholine receptor homolog AChBP in complex with an α-conotoxin PnIA variant", Nat. Struct. Mol. Biol., 12, pp.582~588 (2005)
  24. Dellisanti, C. D., "Crystal structure of the extracellular domain of nAChR α1 bound to α-bungarotoxin at 1.94 Å resolution", Nat. Neurosci., 10, pp.953~962 (2007)
  25. Ulens, C., "Structural determinants of selective α-conotoxin binding to a nicotinic acetylcholine receptor homolog AChBP", Proc. Natl. Acad. Sci. U.S.A., 103, pp.3615~3620 (2006)
  26. Grant, M. A., "Expression and spectroscopic analysis of soluble nicotinic acetylcholine receptor fragments derived from the extracellular domain of the α-subunit", Biochemistry, 38, pp.10730~10742 (1999)
  27. Bren, N., "Hydrophobic pairwise interactions stabilize α-conotoxin MI in the muscle acetylcholine receptor binding site", J. Biol. Chem., 275, pp.12692~12700 (2000)
  28. Chiara, D. C., "Structure of the agonist-binding sites of the torpedo nicotinic acetylcholine receptor: Affinity-labeling and mutational analyses identify γTyr-111", δArg-113 as antagonist affinity determinants, 1999, pp.38, 6689~6698
  29. Quiram, P. A., "Pairwise interactions between neuronal α7acetylcholine receptors and α-conotoxin PnIB", J. Biol. Chem., 275, pp.4889~4896 (2000)
  30. Sugiyama, N., "Residues at the subunit interfaces of the nicotinic acetylcholine receptor that contribute to α-conotoxin M1 binding", Mol. Pharmacol., 53, pp.787~794 (1998)
  31. Dutertre, S., "Determination of α-conotoxin binding modes on neuronal nicotinic acetylcholine receptors", J. Mol. Recogn., 17, pp.339~347 (2004)
  32. Hansen, S. B., "Structures of Aplysia AChBP complexes with nicotinic agonists and antagonists reveal distinctive binding interfaces and conformations", EMBO J., 24, pp.3635~3646 (2005)
  33. Bourne, Y., "Crystal structure of a Cbtx-AChBP complex reveals essential interactions between snake α-neurotoxins and nicotinic receptors", EMBO J., 24, pp.1512~1522 (2005)
  34. Fraenkel, Y., "Nuclear magnetic resonance (NMR) analysis of ligandreceptor interactions: the cholinergic system-a model", CRC,Crit. Rev. Biochem. Mol. Biol., 31, pp.273~301 (1996)
  35. Luo, S., "Single-residue alteration in α-conotoxin PnIA switches its nAChR subtype selectivity", Biochemistry, 38, pp.14542~14548 (1999)
  36. McIntosh, J. M., "Analogs of α-conotoxin MII are selective for α6-containing nicotinic acetylcholine receptors", Mol. Pharmacol., 65, pp.944~952 (2004)
  37. Mok, K. H., "NMR solution conformation of an antitoxic analogue of α-conotoxin GI: identification of a common nicotinic acetylcholine receptor α1-subunit binding surface for small ligands and α-conotoxins", Biochemistry, 38, pp.11895~11904 (1999)
  38. Martí-Renom, M. A., "Comparative protein structure modeling of genes and genomes", Annu. Rev. Biophys. Biomol. Struct., 29, pp.291~325 (2000)
  39. Homer, N., "Local alignment of two-base encoded DNA sequence", BMC Bioinformatics, 10, pp.175~ (2009)
  40. Dutertre, S., "AChBP-targeted α-conotoxin correlates distinct binding orientations with nAChR subtype selectivity", EMBO J., 26, pp.3858~3867 (2007)
  41. Le Novére, N., "Models of the extracellular domain of the nicotinic receptors and of agonist- and Ca2+-binding sites", Proc. Natl. Acad. Sci. U.S.A., 99, pp.3210~3215 (2002)

관련 논문AI추천

분자동역학 전산모사에 의한 α6 nAChR Subunit의 α-conotoxin BuIA에 대한 선택성 연구이명기, Phan Thi HongTham한국수산과학회 · 한국수산과학회지2015 · 제48권 제1호Molecular Mechanisms of Nicergoline from Ergot Fungus in Blocking Human 5-HT3A ReceptorLee Gihyun, Lee Junho H, Moon Myungmi, Pyeon Minsu, Yang Jaehui, Yeom Hye Duck, Yun Jeongyeon한국미생물·생명공학회 · Journal of Microbiology and Biotechnology2025 · 제35권 Solution structure and functional analysis of HelaTx1: the first toxin member of the -KTx5 subfamily김재일, Bong Gyu Park, Jae Ha Ryu, Jan Tytgat, Kazuki Sato, Nao Esaki, Steve Peigneur, Yoko Yamaguchi생화학분자생물학회 · BMB Reports2020 · 제53권 제5호Soluble expression, purification and the role of C-terminal glycine residues in scorpion toxin BmK AGP-SYPU2Chunfu Wu, Jinghai Zhang, Rong Zhang, Yongbo Song, Yong Cui, Yongshan Zhao, Zhuo Yang생화학분자생물학회 · BMB Reports2010 · 제43권 제12호Role of Nicotinic Acetylcholine Receptor on Efferent Inhibition in Cochlear Hair Cell임기정대한청각학회 · Journal of Audiology & Otology2012 · 제16권 제3호3D Structure of STAM1 UIM-ubiquitin Complex Using RosettaDock손우성, 안희철, 이진규, Jong-Jae Yi, Jongsoo Lim한국자기공명학회 · Journal of the Korean Magnetic Resonance Society2011 · 제15권 제1호

이 간행물의 다른 논문 (8건)

Biological activities of lignin hydrolysate-related compoundsSiseon Lee, Robert James Mitchell, Ajay Kalanjana Monnappapp. 265-274Effect of interferon-γ on the fusion of mononuclear osteoclasts into bone-resorbing osteoclasts이명수, 곽한복, 김정우, Ha Young Kim, 오재민, 채수욱, 이창훈pp. 281-286FGF-2 inhibits TNF-α mediated apoptosis through upregulation of Bcl2-A1 and Bcl-xL in ATDC5 cellsJoong-Kook Choi, Hey-Ryun Kim, Youn-Moo Heo, Kyoung-Il Jeong, Hae Lan Jang, Kwang-Yeol Lee, Chang-Yeol Yeo, Hak-Kyo Lee, Seung-Ryul Kim, Eung-Gook Kim, Yong-Min Kim, Sung Hoon Kimpp. 287-292Molecular characterization and immunohistochemical localization of a mitogen-activated protein kinase, Accp38b, from Apis cerana ceranaXingqi Guo, Baohua Xu, Fei Meng, Liang Zhang, Mingjiang Kang, Yuzhen Lipp. 293-298High sensitivity of embryonic stem cells to proteasome inhibitors correlates with low expression of heat shock protein and decrease of pluripotent cell marker expressionYang-Hwa Ha, 김영은, 이영희, 권형주, Jeong-A Parkpp. 299-304
원문 보기