NTSR1的结构动力学和变构效应研究
Study on Structural Dynamics and Allosteric Effects of NTSR1
摘要: 神经降压素受体-1 (the neurotensin receptor 1, NTSR1)是一种G蛋白偶联受体(G-protein-coupled receptor, GPCR)，通过响应胞外侧的刺激重排受体的中间层，在胞内侧形成一个容纳效应蛋白的空腔。NTSR1在中枢神经系统、心血管系统、胃肠道消化系统中表现出重要的生物学活性，是关键的药物靶点。基于各向异性网络模型(anisotropic network model, ANM)，本文系统地分析了NTSR1的结构动力学和变构效应。通过计算慢运动和快运动模式下残基的均方涨落及运动相关性，识别出了与受体结构稳定性和信号转导相关的重要残基，揭示了保守基序间的协同关联。微扰响应扫描(perturbation-response scanning, PRS)给出了残基的敏感–效应性矩阵，描述了受体内的变构通讯网络。这项工作有助于深入对NTSR1功能机制的理解，为基于结构的药物设计提供了理论指导。
Abstract: The neurotensin receptor 1 (NTSR1) is a G-protein-coupled receptor (GPCR). GPCRs rearrange the middle layer of the receptor in response to extracellular stimuli to form a cavity on the intracellular side that accommodates effector proteins. NTSR1 exhibits important biological activities in the central nervous system, cardiovascular system, and gastrointestinal digestive system, being an important drug target. In this work, the structural dynamics and allosteric effects of NTSR1 are systematically analyzed through the anisotropic network model (ANM). The important residues related to structural stability and signal transduction patterns of the receptor are identified by theresidual mean square fluctuation for slow and fast motion modes. Motion correlation analysis reveals positively correlated motions between conserved motifs in class A GPCRs. The sensitivity-response matrix obtained by perturbation-response scanning (PRS) describes the allosteric communication network within the receptor. This work contributes to a deeper understanding of the functional mechanism of NTSR1 and provides theoretical guidance for structure-based drug design.
文章引用：司沁晨, 吴志祥, 李春华. NTSR1的结构动力学和变构效应研究[J]. 生物医学, 2024, 14(2): 251-259. https://doi.org/10.12677/hjbm.2024.142028

参考文献

[1] Santos, R., Ursu, O., Gaulton, A., Bento, A.P., Donadi, R.S., Bologa, C.G. and Oprea, T.I. (2017) A Comprehensive Map of Molecular Drug Targets. Nature Reviews Drug Discovery, 16, 19-34. [Google Scholar] [CrossRef] [PubMed]
[2] Kalafatakis, K. and Triantafyllou, K. (2011) Contribution of Neurotensin in the Immune and Neuroendocrine Modulation of Normal and Abnormal Enteric Function. Regulatory Peptides, 170, 7-17. [Google Scholar] [CrossRef] [PubMed]
[3] St-Gelais, F., Jomphe, C. and Trudeau, L.-É. (2006) The Role of Neurotensin in Central Nervous System Pathophysiology: What Is the Evidence? Journal of Psychiatry and Neuroscience, 31, 229-245.
[4] Boules, M., Li, Z., Smith, K., Fredrickson, P. and Richelson, E. (2013) Diverse Roles of Neurotensin Agonists in the Central Nervous System. Frontiers in endocrinology, 4, Article 36. [Google Scholar] [CrossRef] [PubMed]
[5] Mustain, W.C., Rychahou, P.G. and Evers, B.M. (2011) The Role of Neurotensin in Physiologic and Pathologic Processes. Current Opinion in Endocrinology, Diabetes and Obesity, 18, 75-82. [Google Scholar] [CrossRef] 
[6] White, J.F., Noinaj, N., Shibata, Y., Love, J., Kloss, B., Xu, F. and Tate, C.G. (2012) Structure of the Agonist-Bound Neurotensin Receptor. Nature, 490, 508-513. [Google Scholar] [CrossRef] [PubMed]
[7] Kato, H.E., Zhang, Y., Hu, H., Suomivuori, C.-M., Kadji, F.M.N., Aoki, J. and Huang, W. (2019) Conformational Transitions of a Neurotensin Receptor 1—Gi1 Complex. Nature, 572, 80-85. [Google Scholar] [CrossRef] [PubMed]
[8] Lee, S., Bhattacharya, S., Tate, C.G., Grisshammer, R. and Vaidehi, N. (2015) Structural Dynamics and Thermostabilization of Neurotensin Receptor 1. The Journal of Physical Chemistry B, 119, 4917-4928. [Google Scholar] [CrossRef] [PubMed]
[9] Cong, X., Fiorucci, S. and Golebiowski, J. (2018) Activation Dynamics of the Neurotensin G Protein-Coupled Receptor 1. Journal of Chemical Theory and Computation, 14, 4467-4473. [Google Scholar] [CrossRef] [PubMed]
[10] Nagarajan, S., Alkayed, N.J., Kaul, S. and Barnes, A.P. (2020) Effect of Thermostable Mutations on the Neurotensin Receptor 1 (NTSR1) Activation State. Journal of Biomolecular Structure and Dynamics, 38, 340-353. [Google Scholar] [CrossRef] [PubMed]
[11] Bahar, I., Atilgan, A.R. and Erman, B. (1997) Direct Evaluation of Thermal Fluctuations in Proteins Using a Single-Parameter Harmonic Potential. Folding and Design, 2, 173-181. [Google Scholar] [CrossRef] 
[12] Atilgan, A.R., Durell, S., Jernigan, R.L., Demirel, M.C., Keskin, O. and Bahar, I. (2001) Anisotropy of Fluctuation Dynamics of Proteins with an Elastic Network Model. Biophysical Journal, 80, 505-515. [Google Scholar] [CrossRef] 
[13] Bahar, I., Atilgan, A.R., Demirel, M.C. and Erman, B. (1998) Vibrational Dynamics of Folded Proteins: Significance of Slow and Fast Motions in Relation to Function and Stability. Physical Review Letters, 80, Article 2733. [Google Scholar] [CrossRef] 
[14] Gong, W., Liu, Y., Zhao, Y., Wang, S., Han, Z. and Li, C. (2021) Equally Weighted Multiscale Elastic Network Model and Its Comparison with Traditional and Parameter-Free Models. Journal of Chemical Information and Modeling, 61, 921-937. [Google Scholar] [CrossRef] [PubMed]
[15] Penkler, D., Sensoy, O.Z., Atilgan, C. and Tastan Bishop, O.Z. (2017) Perturbation-Response Scanning Reveals Key Residues for Allosteric Control in Hsp70. Journal of Chemical Information and Modeling, 57, 1359-1374. [Google Scholar] [CrossRef] [PubMed]
[16] Deluigi, M., Klipp, A., Klenk, C., Merklinger, L., Eberle, S.A., Morstein, L. and Kamenecka, T.M. (2021) Complexes of the Neurotensin Receptor 1 with Small-Molecule Ligands Reveal Structural Determinants of Full, Partial, and Inverse Agonism. Science Advances, 7, eabe5504. [Google Scholar] [CrossRef] [PubMed]
[17] Ballesteros, J.A. and Weinstein, H. (1995) Integrated Methods for the Construction of Three-Dimensional Models and Computational Probing of Structure-Function Relations in G Protein-Coupled Receptors Methods in Neurosciences, 25, 366-428. [Google Scholar] [CrossRef] 
[18] Dutta, A., Krieger, J., Lee, J.Y., Garcia-Nafria, J., Greger, I.H. and Bahar, I. (2015) Cooperative Dynamics of Intact AMPA and NMDA Glutamate Receptors: Similarities and Subfamily-Specific Differences. Structure, 23, 1692-1704. [Google Scholar] [CrossRef] [PubMed]
[19] 陈磊, 巩卫康, 李春华. 基于各向异性网络模型研究δ阿片受体的动力学与关键残基[J]. 生物化学与生物物理进展, 2022, 49(6): 1146-1154.
[20] Martin, S., Botto, J.-M., Vincent, J.-P. and Mazella, J. (1999) Pivotal Role of an Aspartate Residue in Sodium Sensitivity and Coupling to G Proteins of Neurotensin Receptors. Molecular Pharmacology, 55, 210-215. [Google Scholar] [CrossRef] [PubMed]
[21] Krumm, B.E., White, J.F., Shah, P. and Grisshammer, R. (2015) Structural Prerequisites for G-Protein Activation by the Neurotensin Receptor. Nature Communications, 6, Article No. 7895. [Google Scholar] [CrossRef] [PubMed]
[22] Filipek, S. (2019) Molecular Switches in GPCRs. Current Opinion in Structural Biology, 55, 114-120. [Google Scholar] [CrossRef] [PubMed]
[23] Trzaskowski, B., Latek, D., Yuan, S., Ghoshdastider, U., Debinski, A. and Filipek, S. (2012) Action of Molecular Switches in GPCRs-Theoretical and Experimental Studies. Current Medicinal Chemistry, 19, 1090-1109. [Google Scholar] [CrossRef] [PubMed]
[24] Egloff, P., Hillenbrand, M., Klenk, C., Batyuk, A., Heine, P., Balada, S. and Plückthun, A. (2014) Structure of Signaling-Competent Neurotensin Receptor 1 Obtained by Directed Evolution in Escherichia Coli. Proceedings of the National Academy of Sciences, 111, E655-E662. [Google Scholar] [CrossRef] [PubMed]
[25] Krumm, B.E., Lee, S., Bhattacharya, S., Botos, I., White, C.F., Du, H. and Grisshammer, R. (2016) Structure and Dynamics of a Constitutively Active Neurotensin Receptor. Scientific reports, 6, Article 38564. [Google Scholar] [CrossRef] [PubMed]
[26] Wheatley, M., Wootten, D., Conner, M.T., Simms, J., Kendrick, R., Logan, R.T. and Barwell, J. (2012) Lifting the Lid on GPCRs: The Role of Extracellular Loops. British Journal of Pharmacology, 165, 1688-1703. [Google Scholar] [CrossRef] [PubMed]
[27] Yin, W., Li, Z., Jin, M., Yin, Y.-L., De Waal, P.W., Pal, K. and Gao, J. (2019) A Complex Structure of Arrestin-2 Bound to a G Protein-Coupled Receptor. Cell Research, 29, 971-983. [Google Scholar] [CrossRef] [PubMed]

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