Entry from the Lipid Bilayer: A Possible Pathway for Inhibition of a Peptide G Protein-Coupled Receptor by a Lipophilic Small Molecule.
Entry from the Lipid Bilayer: A Possible Pathway for Inhibition of a Peptide G Protein-Coupled Receptor by a Lipophilic Small Molecule.
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DOI：
10.1021/acs.biochem.8b00577
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发表时间：
2018-10-02
期刊：
影响因子：
2.9
通讯作者：
Coughlin SR
中科院分区：
文献类型：
--
作者：
Bokoch MP;Jo H;Valcourt JR;Srinivasan Y;Pan AC;Capponi S;Grabe M;Dror RO;Shaw DE;DeGrado WF;Coughlin SR
G蛋白偶联受体（GPCR）配体与受体结合或解离的途径在很大程度上是未知的。蛋白酶激活受体-1（PAR 1）是一种GPCR，通过凝血酶裂解暴露的系留激动剂肽的分子内结合激活。相比之下，PAR 1拮抗剂vorapaxar是一种亲脂性药物，其结合在几乎完全与细胞外溶剂隔绝的口袋中。vorapaxar的结合和解离途径尚不清楚。从与PAR 1结合的vorapaxar的晶体结构开始，我们进行了配体解离的温度加速分子动力学模拟。在大多数模拟中，vorapaxar通过跨膜螺旋（TM）束中的开口横向退出受体进入脂质双层。在完全解离之前，vorapaxar暂停在通过与受体和脂质头基的相互作用而稳定的亚稳态中间体中。具有预测在TM 6和TM 7之间延伸到脂质双层中的烷基链的伏拉帕沙衍生物抑制PAR 1，其在细胞信号传导测定中具有与母体化合物相似的表观开启速率。这些数据与vorapaxar通过从脂质双层通过TM 6和TM 7之间的途径与PAR 1结合一致，与分子动力学观察到的最一致的途径一致。虽然有一些证据表明配体进入视紫红质和脂质激活的GPCR从细胞膜，我们的研究提供了肽激活的GPCR的第一个这样的证据，并表明，亚稳态中间体沿着药物结合和解离途径可以通过脂质和配体之间的特异性相互作用稳定。
The pathways that G protein-coupled receptor (GPCR) ligands follow as they bind to or dissociate from their receptors are largely unknown. Protease-activated receptor-1 (PAR1) is a GPCR activated by intramolecular binding of a tethered agonist peptide that is exposed by thrombin cleavage. By contrast, the PAR1 antagonist vorapaxar is a lipophilic drug that binds in a pocket almost entirely occluded from the extracellular solvent. The binding and dissociation pathway of vorapaxar is unknown. Starting with the crystal structure of vorapaxar bound to PAR1, we performed temperature-accelerated molecular dynamics simulations of ligand dissociation. In the majority of simulations, vorapaxar exited the receptor laterally into the lipid bilayer through openings in the transmembrane helix (TM) bundle. Prior to full dissociation, vorapaxar paused in metastable intermediates stabilized by interactions with the receptor and lipid headgroups. Derivatives of vorapaxar with alkyl chains predicted to extend between TM6 and TM7 into the lipid bilayer inhibited PAR1 with apparent on rates similar to that of the parent compound in cell signaling assays. These data are consistent with vorapaxar binding to PAR1 via a pathway that passes between TM6 and TM7 from the lipid bilayer, in agreement with the most consistent pathway observed by molecular dynamics. While there is some evidence of entry of the ligand into rhodopsin and lipid-activated GPCRs from the cell membrane, our study provides the first such evidence for a peptide-activated GPCR and suggests that metastable intermediates along drug binding and dissociation pathways can be stabilized by specific interactions between lipids and the ligand.
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影响因子：
3.9
作者：
Ghosal, Anima;Lu, Xiaowen;Alton, Kevin B.
通讯作者：
Alton, Kevin B.
影响因子：
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作者：
Pfreundschuh M;Alsteens D;Wieneke R;Zhang C;Coughlin SR;Tampé R;Kobilka BK;Müller DJ
通讯作者：
Müller DJ
影响因子：
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作者：
Hurst, Dow P.;Grossfield, Alan;Reggio, Patricia H.
通讯作者：
Reggio, Patricia H.
DOI：
10.1146/annurev-pharmtox-032112-135923
发表时间：
2013
影响因子：
12.5
作者：
Katritch V;Cherezov V;Stevens RC
通讯作者：
Stevens RC
DOI：
10.1126/science.1197410
发表时间：
2010-11-19
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Chien EY;Liu W;Zhao Q;Katritch V;Han GW;Hanson MA;Shi L;Newman AH;Javitch JA;Cherezov V;Stevens RC
通讯作者：
Stevens RC