Structure of the human κ-opioid receptor in complex with JDTic.
Structure of the human κ-opioid receptor in complex with JDTic.
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DOI：
10.1038/nature10939
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发表时间：
2012-03-21
期刊：
影响因子：
64.8
通讯作者：
Stevens, Raymond C.
中科院分区：
文献类型：
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作者：
Wu, Huixian;Wacker, Daniel;Mileni, Mauro;Katritch, Vsevolod;Han, Gye Won;Vardy, Eyal;Liu, Wei;Thompson, Aaron A.;Huang, Xi-Ping;Carroll, F. Ivy;Mascarella, S. Wayne;Westkaemper, Richard B.;Mosier, Philip D.;Roth, Bryan L.;Cherezov, Vadim;Stevens, Raymond C.
阿片受体介导内源性和外源性阿片类物质对许多基本生理过程的作用，包括对疼痛、呼吸驱动、情绪的调节，对于κ-阿片受体(KOR)，还有烦躁不安和精神错乱。本文报道了人KOR(HKOR)与选择性拮抗剂JDTic在2.9埃分辨率下以平行二聚体排列的络合物的晶体结构。该结构揭示了配体结合口袋的重要特征，这有助于JDTic对hKOR的高亲和力和亚型选择性。对其他重要的KOR选择性配体的建模，包括吗啡衍生的拮抗剂Nor-BNI和GNTI，以及二萜激动剂Salvinorin A类似物RB-，揭示了结合这些不同化学类型的共同和不同的特征。定点突变和配体构效关系的分析证实了晶体结构中观察到的相互作用，从而为hKOR亚型选择性提供了分子解释，并为设计具有新药理性质的hKOR化合物提供了必要的见解。
Opioid receptors (ORs) mediate the actions of endogenous and exogenous opioids for many essential physiological processes including regulation of pain, respiratory drive, mood, and, in the case of κ-opioid receptors (KOR), dysphoria and psychotomimesis. Here we report the crystal structure of the human KOR (hKOR) in complex with the selective antagonist JDTic, arranged in parallel-dimers, at 2.9 angstrom resolution. The structure reveals important features of the ligand binding pocket that contribute to JDTic’s high affinity and subtype-selectivity for hKOR. Modeling of other important KOR-selective ligands, including the morphinan-derived antagonists nor-BNI and GNTI, and the diterpene agonist salvinorin A analog RB-64, reveals both common and distinct features for binding these diverse chemotypes. Analysis of site-directed mutagenesis and ligand structure-activity relationships confirms the interactions observed in the crystal structure, thereby providing a molecular explanation for hKOR subtype-selectivity along with insight essential for the design of hKOR compounds with new pharmacological properties.
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影响因子：
13.5
作者：
Carlezon WA Jr;Béguin C;Knoll AT;Cohen BM
通讯作者：
Cohen BM
影响因子：
5.7
作者：
Kufareva, Irina;Rueda, Manuel;Katritch, Vsevolod;Stevens, Raymond C.;Abagyan, Ruben;Yoshikawa, Yasushi;Furuya, Toshio;Lee, Huisun;Roy, Ambrish;Grime, John;Rebehmed, Joseph;Zhang, Yang;Roumen, Luc;de Esch, Iwan J. P.;Leurs, Rob;de Graaf, Chris;Li, Youyong;Hou, Tingjun;Mysinger, Michael M.;Weiss, Dahlia R.;Irwin, John J.;Shoichet, Brian K.;McRobb, Fiona M.;Capuano, Ben;Crosby, Ian T.;Chalmers, David K.;Yuriev, Elizabeth;Wang, Qi;Mach, Robert H.;Reichert, David E.;Chuang, Gwo-Yu;Rognan, Didier;Simms, John;Sexton, Patrick;Wootten, Denise;Latek, Dorota;Ghoshdastider, Umesh;Filipek, Slawomir;Kirkpatrick, Andrea;Trzaskowski, Bartosz;Griffith, Adam;Kim, Soo-Kyung;Abrol, Ravinder;Goddard, William A., III;Vaidehi, Nagarajan;Lam, Alfonso;Bhattacharya, Supriyo;Li, Hubert;Balaraman, Gouthaman;Niesen, Michiel;Pal, Sandeep;Vorobjev, Yrii;Bakulina, Natalia;Solovyev, Victor;Beuming, Thijs;Costanzi, Stefano;Shi, Lei;Higgs, Chris;Salam, Noeris;Lupyan, Dmitry;Sherman, Woody;Ding, Feng;Kota, Pradeep;Ramachandran, Srinivas;Dokholyan, Nikolay V.;Carlsson, Jens;Coleman, Ryan G.;Fan, Hao;Schlessinger, Avner;Sali, Andrej;Tikhonova, Irina;Pogozheva, Irina;Lomize, Andrei;Hall, Nathan E.;Muddassar, Muhammad;Zhang, Yang;Pae, Ae Nim;Lee, Jooyoung;Lopez, Laura;Obiol-Pardo, Cristian;Selent, Jana;Mahboob, Sadia;Werner, Tim;Church, W. Bret;Brylinski, Michal;Ando, Tadashi;Guerler, Aysam;Zhou, Hongyi;Skolnick, Jeffrey;Xhaard, Henri;Jurkowski, Wiktor;Elofsson, Arne;Murad, Ahsan K.;Drwal, Malgorzata;Dupree, Tom B.;Griffith, Renate;Ostopovici-Halip, Liliana;Bologa, Cristian;Chen, K. M.;Sun, J.;Barth, Patrick;Yarov-Yarovoy, Vladimir;Baker, David;Vroling, Bas;Sanders, Marijn P. A.;Nabuurs, Sander B.;Nikiforovich, Gregory V.
通讯作者：
Nikiforovich, Gregory V.
DOI：
10.1073/pnas.78.10.6543
发表时间：
1981-01-01
期刊：
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA-BIOLOGICAL SCIENCES
影响因子：
--
作者：
CHAVKIN, C;GOLDSTEIN, A
通讯作者：
GOLDSTEIN, A
DOI：
10.1107/s0907444909052925
发表时间：
2010-02
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Adams PD;Afonine PV;Bunkóczi G;Chen VB;Davis IW;Echols N;Headd JJ;Hung LW;Kapral GJ;Grosse-Kunstleve RW;McCoy AJ;Moriarty NW;Oeffner R;Read RJ;Richardson DC;Richardson JS;Terwilliger TC;Zwart PH
通讯作者：
Zwart PH
影响因子：
14.8
作者：
通讯作者：
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