Comparison of cyclooxygenase-1 crystal structures: cross-talk between monomers comprising cyclooxygenase-1 homodimers.
Comparison of cyclooxygenase-1 crystal structures: cross-talk between monomers comprising cyclooxygenase-1 homodimers.
复制标题
DOI：
10.1021/bi1003298
复制
发表时间：
2010-08-24
期刊：
影响因子：
2.9
通讯作者：
Smith, William L.
中科院分区：
文献类型：
--
作者：
Sidhu, Ranjinder S.;Lee, Jullia Y.;Yuan, Chong;Smith, William L.
前列腺素内过氧化物 H 合酶 (PGHS)-1 和 -2（也称为环氧合酶 (COX)-1 和 -2）催化前列腺素生物合成的关键步骤。两种异构体都是非甾体抗炎药 (NSAID) 的靶标。 PGHS 是同源二聚体，具有半位点 COX 活性；此外，一些非甾体抗炎药通过仅结合一种单体而引起酶抑制。为了更多地了解组成每个 PGHS-1 二聚体的单体之间必然发生的串扰，我们分析了在五种不同条件下结晶的 PGHS-1 的结构，包括不存在任何紧密结合配体以及存在非特异性 NSAID 和 COX-2 抑制剂的情况。当与亚化学计量的 NSAID 一起结晶时，两种单体通常都被抑制剂完全占据；因此，酶更喜欢以完全占据的形式结晶。在比较五个结构时，我们仅观察到残基123-129和残基510-515的位置变化。在一个单体被 NSAID 完全占据而伴侣单体不完全占据的情况下，在部分占据的单体中会看到涉及残基 123-129 的环的替代构象。根据这一观察结果和之前的交联研究，我们认为单体之间的串扰涉及位于二聚体界面的移动 123-129 环。在没有 NSAID 的情况下结晶的羊 PGHS-1 中，底物进入 COX 位点有一条替代途径，不同于众所周知的通过膜结合域的途径。
Prostaglandin endoperoxide H synthases (PGHSs)-1 and -2 (also called cyclooxygenases (COXs)-1 and -2) catalyze the committed step in prostaglandin biosynthesis. Both isoforms are targets of nonsteroidal anti-inflammatory drugs (NSAIDs). PGHSs are homodimers that exhibit half-of-sites COX activity; moreover, some NSAIDs cause enzyme inhibition by binding only one monomer. To learn more about the cross-talk that must be occurring between the monomers comprising each PGHS-1 dimer, we analyzed structures of PGHS-1 crystallized under five different conditions including in the absence of any tightly binding ligand and in the presence of non-specific NSAIDs and of a COX-2 inhibitor. When crystallized with sub-stoichiometric amounts of an NSAID, both monomers are often fully occupied with inhibitor; thus, the enzyme prefers to crystallize in a fully occupied form. In comparing the five structures, we only observe changes in the positions of residues 123-129 and residues 510-515. In cases where one monomer is fully occupied with an NSAID and the partner monomer is incompletely occupied, an alternate conformation of the loop involving residues 123-129 is seen in the partially occupied monomer. We propose, based on this observation and previous cross-linking studies, that cross-talk between monomers involves this mobile 123-129 loop, which is located at the dimer interface. In ovine PGHS-1 crystallized in the absence of an NSAID, there is an alternative route for substrate entry into the COX site different than the well-known route through the membrane binding domain.
登录
查看更多内容
DOI：
10.1107/s0907444905036693
发表时间：
2006-01-01
影响因子：
2.2
作者：
Evans, P
通讯作者：
Evans, P
影响因子：
5.6
作者：
Gupta, K;Selinsky, BS;Loll, PJ
通讯作者：
Loll, PJ
影响因子：
56.9
作者：
Malkowski, MG;Ginell, SL;Garavito, RM
通讯作者：
Garavito, RM
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
14.9
作者：
Davis IW;Leaver-Fay A;Chen VB;Block JN;Kapral GJ;Wang X;Murray LW;Arendall WB 3rd;Snoeyink J;Richardson JS;Richardson DC
通讯作者：
Richardson DC