Analysis of binding site hot spots on the surface of Ras GTPase.
Analysis of binding site hot spots on the surface of Ras GTPase.
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DOI：
10.1016/j.jmb.2011.09.011
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发表时间：
2011-11-04
影响因子：
5.6
通讯作者：
Mattos, Carla
中科院分区：
文献类型：
--
作者：
Buhrman, Greg;O'Connor, Casey;Zerbe, Brandon;Kearney, Bradley M.;Napoleon, Raeanne;Kovrigina, Elizaveta A.;Vajda, Sandor;Kozakov, Dima;Kovrigin, Evgenii L.;Mattos, Carla
我们最近在Ras中发现了一种变构开关，为这种GTdR带来了额外的复杂性，其突变体涉及近30%的癌症。在激活变构开关后，螺旋3/环7中存在与活性位点中的无序到有序转变相关的移位。在这里，我们使用多种溶剂的晶体结构和计算溶剂映射（FTMap）的组合，以确定结合位点的热点在“关”和“开”的GTP结合形式的H-Ras的变构状态。13个站点被揭示，扩展可能的配体结合的靶位点远远超出了活性位点。H和K亚型的FTMAps比较显示基本相同的热点。此外，使用NMR测量自旋弛豫，我们确定K-Ras表现出全球构象动力学非常相似，我们以前报道的H-Ras。因此，我们假设，全球构象重排作为一种机制，效应器接口和远程热点之间的变构耦合在所有Ras亚型。至少在涉及G结构域的结合位点方面，H-Ras是K-Ras和可能的N-Ras的极好模型。Ras作为药物设计的靶点至今仍是难以捉摸的。目前的工作确定了各种未探索的热点在整个表面的Ras，扩展的重点从无序的活性位点，有序的位置，应该更容易为目标。
We have recently discovered an allosteric switch in Ras, bringing an additional level of complexity to this GTPase whose mutants are involved in nearly 30% of cancers. Upon activation of the allosteric switch, there is a shift in helix 3/loop 7 associated with a disorder to order transition in the active site. Here, we use a combination of multiple solvent crystal structures and computational solvent mapping (FTMap) to determine binding site hot spots in the “off” and “on” allosteric states of the GTP-bound form of H-Ras. Thirteen sites are revealed, expanding possible target sites for ligand binding well beyond the active site. Comparison of FTMaps for the H and K isoforms reveals essentially identical hot spots. Furthermore, using NMR measurements of spin relaxation, we determined that K-Ras exhibits global conformational dynamics very similar to those we previously reported for H-Ras. We thus hypothesize that the global conformational rearrangement serves as a mechanism for allosteric coupling between the effector interface and remote hot spots in all Ras isoforms. At least with respect to the binding sites involving the G domain, H-Ras is an excellent model for K-Ras and probably N-Ras as well. Ras has so far been elusive as a target for drug design. The present work identifies various unexplored hot spots throughout the entire surface of Ras, extending the focus from the disordered active site to well-ordered locations that should be easier to target.
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影响因子：
2.2
作者：
CARVER, JP;RICHARDS, RE
通讯作者：
RICHARDS, RE
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：
5.7
作者：
Buhrman, Greg;Wink, Glenna;Mattos, Carla
通讯作者：
Mattos, Carla
DOI：
10.1073/pnas.0903907107
发表时间：
2010-01-19
影响因子：
11.1
作者：
Abankwa, Daniel;Gorfe, Alemayehu A.;Hancock, John F.
通讯作者：
Hancock, John F.
DOI：
10.1107/s0907444998003254
发表时间：
1998-09-01
期刊：
ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY
影响因子：
--
作者：
Brunger, AT;Adams, PD;Warren, GL
通讯作者：
Warren, GL