Structure of the Angiotensin receptor revealed by serial femtosecond crystallography.
Structure of the Angiotensin receptor revealed by serial femtosecond crystallography.
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血管紧张素受体的结构通过串行飞秒晶体学揭示。
DOI：
10.1016/j.cell.2015.04.011
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发表时间：
2015-05-07
期刊：
影响因子：
64.5
通讯作者：
Cherezov V
中科院分区：
文献类型：
--
作者：
Zhang H;Unal H;Gati C;Han GW;Liu W;Zatsepin NA;James D;Wang D;Nelson G;Weierstall U;Sawaya MR;Xu Q;Messerschmidt M;Williams GJ;Boutet S;Yefanov OM;White TA;Wang C;Ishchenko A;Tirupula KC;Desnoyer R;Coe J;Conrad CE;Fromme P;Stevens RC;Katritch V;Karnik SS;Cherezov V
血管紧张素II 1型受体(AT1R)是一种G蛋白偶联受体，是维持血压的主要调节剂。尽管一些抗高血压药物已经被开发为AT1R阻滞剂(ARB)，但AT1R配体结合和调控的结构基础仍然难以捉摸，主要是由于生长高质量晶体用于同步辐射结构测定的困难。应用最近发展起来的X射线自由电子激光连续飞秒结晶学方法，我们成功地测定了人AT1R与其选择性拮抗剂ZD7155在2.9？分辨率下的络合物的晶体结构。AT1R-ZD7155复合结构揭示了AT1R的关键结构特征和ZD7155结合的关键相互作用。临床使用的ARB与AT1R结构的对接模拟进一步阐明了这些抗高血压药物的共同和不同的结合模式。因此，我们的结果为AT1R结构-功能关系和基于结构的药物设计提供了基本的见解。
Angiotensin II type 1 receptor (AT1R) is a G protein-coupled receptor that serves as a primary regulator for blood pressure maintenance. Although several anti-hypertensive drugs have been developed as AT1R blockers (ARBs), the structural basis for AT1R ligand-binding and regulation has remained elusive, mostly due to the difficulties of growing high quality crystals for structure determination using synchrotron radiation. By applying the recently developed method of serial femtosecond crystallography at an X-ray free-electron laser, we successfully determined the room-temperature crystal structure of the human AT1R in complex with its selective antagonist ZD7155 at 2.9 Å resolution. The AT1R-ZD7155 complex structure revealed key structural features of AT1R and critical interactions for ZD7155 binding. Docking simulations of the clinically used ARBs into the AT1R structure further elucidated both the common and distinct binding modes for these anti-hypertensive drugs. Our results thereby provide fundamental insights into AT1R structure-function relationship and structure-based drug design.
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DOI：
10.1126/science.1244142
发表时间：
2013-12-20
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Liu W;Wacker D;Gati C;Han GW;James D;Wang D;Nelson G;Weierstall U;Katritch V;Barty A;Zatsepin NA;Li D;Messerschmidt M;Boutet S;Williams GJ;Koglin JE;Seibert MM;Wang C;Shah ST;Basu S;Fromme R;Kupitz C;Rendek KN;Grotjohann I;Fromme P;Kirian RA;Beyerlein KR;White TA;Chapman HN;Caffrey M;Spence JC;Stevens RC;Cherezov V
通讯作者：
Cherezov V
影响因子：
14.8
作者：
通讯作者：
--
影响因子：
6.1
作者：
Barty A;Kirian RA;Maia FR;Hantke M;Yoon CH;White TA;Chapman H
通讯作者：
Chapman H
影响因子：
14.8
作者：
Liu, Wei;Ishchenko, Andrii;Cherezov, Vadim
通讯作者：
Cherezov, Vadim
影响因子：
4.8
作者：
Miura, S;Zhang, JL;Karnik, SS
通讯作者：
Karnik, SS