Critical Role for Polar Residues in Coupling Leukotriene B4 Binding to Signal Transduction in BLT1*
Critical Role for Polar Residues in Coupling Leukotriene B4 Binding to Signal Transduction in BLT1*
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极性残基在白三烯 B4 结合与 BLT1* 信号转导偶联中的关键作用
DOI：
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发表时间：
2007
影响因子：
4.8
通讯作者：
B. Haribabu
中科院分区：
文献类型：
--
作者：
S. Basu;V. Jala;Steven P. Mathis;Soujanya T Rajagopal;A. Del Prete;P. Maturu;J. Trent;B. Haribabu
Leukotriene B4 (LTB4) mediates a variety of inflammatory diseases such as asthma, arthritis, atherosclerosis, and cancer through activation of the G-protein-coupled receptor, BLT1. Using in silico molecular dynamics simulations combined with site-directed mutagenesis we characterized the ligand binding site and activation mechanism for BLT1. Mutation of residues predicted as potential ligand contact points in transmembrane domains (TMs) III (H94A and Y102A), V (E185A), and VI (N241A) resulted in reduced binding affinity. Analysis of arginines in extracellular loop 2 revealed that mutating arginine 156 but not arginine 171 or 178 to alanine resulted in complete loss of LTB4 binding to BLT1. Structural models for the ligand-free and ligand-bound states of BLT1 revealed an activation core formed around Asp-64, displaying multiple dynamic interactions with Asn-36, Ser-100, and Asn-281 and a triad of serines, Ser-276, Ser-277, and Ser-278. Mutagenesis of many of these residues in BLT1 resulted in loss of signaling capacity while retaining normal LTB4 binding function. Thus, polar residues within TMs III, V, and VI and extracellular loop 2 are critical for ligand binding, whereas polar residues in TMs II, III, and VII play a central role in transducing the ligand-induced conformational change to activation. The delineation of a validated binding site and activation mechanism should facilitate structure-based design of inhibitors targeting BLT1.
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影响因子：
2.9
作者：
Altenbach, C;Yang, K;Hubbell, WL
通讯作者：
Hubbell, WL
DOI：
10.1164/rccm.200502-205oc
发表时间：
2005-07-15
影响因子：
24.7
作者：
Miyahara, N;Takeda, K;Gelfand, EW
通讯作者：
Gelfand, EW
DOI：
10.1073/pnas.0401429101
发表时间：
2004-05-11
影响因子：
11.1
作者：
Rader, AJ;Anderson, G;Klein-Seetharaman, J
通讯作者：
Klein-Seetharaman, J
影响因子：
2.9
作者：
Wang, Junmei;Wang, Wei;Case, David A.
通讯作者：
Case, David A.