Conserved binding mode of human beta2 adrenergic receptor inverse agonists and antagonist revealed by X-ray crystallography.
Conserved binding mode of human beta2 adrenergic receptor inverse agonists and antagonist revealed by X-ray crystallography.
复制标题
DOI：
10.1021/ja105108q
复制
发表时间：
2010-08-25
影响因子：
15
通讯作者：
Stevens, Raymond C.
中科院分区：
文献类型：
--
作者：
Wacker, Daniel;Fenalti, Gustavo;Brown, Monica A.;Katritch, Vsevolod;Abagyan, Ruben;Cherezov, Vadim;Stevens, Raymond C.
G蛋白偶联受体（GPCRs）是目前药物作用靶点的主要组成部分，其中β 2肾上腺素能受体（β2AR）是研究最多的一种。以前，β2AR的X射线晶体结构已经在与两种部分反向激动剂的复合物中确定，但是其他配体对结构的整体影响或对结合位点的局部影响尚未得到很好的理解。为了评估这种配体诱导的构象差异的程度，我们确定了先前描述的工程化β2AR构建体与两种反向激动剂复合的晶体结构：ICI 118，551（2.8 μ g），最近描述的化合物（2.8 μ g）（Kolb et al，2009）和拮抗剂阿普洛尔（3.1 μ g）。这些结构显示出与先前β2AR结构相同的总体折叠，并证明配体结合位点可以容纳具有不同化学和药理学性质的化合物，仅具有轻微的局部结构重排。所有三种化合物均含有与受体建立保守氢键网络的羟胺基序和与β2AR形成不同相互作用的化学多样性芳香族部分。此外，受体配体交叉对接实验表明，单个β2AR复合物可以适用于一系列拮抗剂和反向激动剂的对接，但也表明额外的配体-受体结构可能有助于进一步提高药物设计中的计算机对接或先导优化的性能。
G protein-coupled receptors (GPCRs) represent a large fraction of current pharmaceutical targets, and of the GPCRs, the β2adrenergic receptor (β2AR) is one of the most extensively studied. Previously, the X-ray crystal structure of β2AR has been determined in complex with two partial inverse agonists, but the global impact of additional ligands on the structure or local impacts on the binding site are not well-understood. To assess the extent of such ligand-induced conformational differences, we determined the crystal structures of a previously described engineered β2AR construct in complex with two inverse agonists: ICI 118,551 (2.8 Å), a recently described compound (2.8 Å) (Kolb et al, 2009), and the antagonist alprenolol (3.1 Å). The structures show the same overall fold observed for the previous β2AR structures and demonstrate that the ligand binding site can accommodate compounds of different chemical and pharmacological properties with only minor local structural rearrangements. All three compounds contain a hydroxy-amine motif that establishes a conserved hydrogen bond network with the receptor and chemically diverse aromatic moieties that form distinct interactions with β2AR. Furthermore, receptor ligand cross-docking experiments revealed that a single β2AR complex can be suitable for docking of a range of antagonists and inverse agonists but also indicate that additional ligand−receptor structures may be useful to further improve performance forin-silicodocking or lead-optimization in drug design.
登录
查看更多内容
影响因子：
2.9
作者：
Devanathan, S;Yao, ZP;Tollin, G
通讯作者：
Tollin, G
影响因子：
14.8
作者：
Audet, Martin;Bouvier, Michel
通讯作者：
Bouvier, Michel
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
3
作者：
Vilar, Santiago;Karpiak, Joel;Costanzi, Stefano
通讯作者：
Costanzi, Stefano
DOI：
10.1073/pnas.0812657106
发表时间：
2009-04-21
影响因子：
11.1
作者：
Kolb, Peter;Rosenbaum, Daniel M.;Shoichet, Brian K.
通讯作者：
Shoichet, Brian K.