Crystal structures of the catalytic domain of human soluble guanylate cyclase.
Crystal structures of the catalytic domain of human soluble guanylate cyclase.
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DOI：
10.1371/journal.pone.0057644
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Gileadi O
中科院分区：
文献类型：
--
作者：
Allerston CK;von Delft F;Gileadi O
可溶性鸟苷酸环化酶 (sGC) 响应一氧化氮催化环状 GMP 的合成。该酶是同源α和β亚基的异二聚体，每个亚基由多个结构域组成。我们在此展示了 α 和 β 亚基催化域的异二聚体以及 β 亚基的无活性同二聚体的晶体结构。后生动物异聚环化酶的第一个结构提供了一些观察结果。首先，这些结构在整体折叠和保守活性位点残基的排列方面类似于腺苷酸环化酶和其他鸟苷酸环化酶的已知结构，这些残基由界面处的两个亚基贡献。其次，亚基相互作用表面是混杂的，允许同二聚体和异聚体缔合；全长酶对异二聚体形成的偏好必须源自其他相互作用界面的综合贡献。第三，异二聚体结构处于非活性构象，但可以通过涉及α亚基26°刚体旋转的结构转变叠加到腺苷酸环化酶的活性构象上。在建模的活性构象中，亚基界面中的大多数活性位点残基与腺苷酸环化酶的残基精确对齐。最后，建模的活性构象还通过伪对称性揭示了与活性位点相关的空腔。假对称位点缺乏关键活性位点残基，但可以以类似于毛喉素与腺苷酸环化酶结合的方式结合变构调节剂。这表明有可能开发一类针对催化结构域的新型鸟苷酸环化酶活性小分子调节剂。
Soluble guanylate cyclase (sGC) catalyses the synthesis of cyclic GMP in response to nitric oxide. The enzyme is a heterodimer of homologous α and β subunits, each of which is composed of multiple domains. We present here crystal structures of a heterodimer of the catalytic domains of the α and β subunits, as well as an inactive homodimer of β subunits. This first structure of a metazoan, heteromeric cyclase provides several observations. First, the structures resemble known structures of adenylate cyclases and other guanylate cyclases in overall fold and in the arrangement of conserved active-site residues, which are contributed by both subunits at the interface. Second, the subunit interaction surface is promiscuous, allowing both homodimeric and heteromeric association; the preference of the full-length enzyme for heterodimer formation must derive from the combined contribution of other interaction interfaces. Third, the heterodimeric structure is in an inactive conformation, but can be superposed onto an active conformation of adenylate cyclase by a structural transition involving a 26° rigid-body rotation of the α subunit. In the modelled active conformation, most active site residues in the subunit interface are precisely aligned with those of adenylate cyclase. Finally, the modelled active conformation also reveals a cavity related to the active site by pseudo-symmetry. The pseudosymmetric site lacks key active site residues, but may bind allosteric regulators in a manner analogous to the binding of forskolin to adenylate cyclase. This indicates the possibility of developing a new class of small-molecule modulators of guanylate cyclase activity targeting the catalytic domain.
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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
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
DOI：
10.1111/j.1432-1033.1990.tb15572.x
发表时间：
1990-06-20
期刊：
EUROPEAN JOURNAL OF BIOCHEMISTRY
影响因子：
--
作者：
HUMBERT, P;NIROOMAND, F;BOHME, E
通讯作者：
BOHME, E
影响因子：
4.8
作者：
Linder, JU;Hoffmann, T;Schultz, JE
通讯作者：
Schultz, JE
影响因子：
2.9
作者：
Lamothe, M;Chang, FJ;Beuve, A
通讯作者：
Beuve, A