A cryptic pocket in Ebola VP35 allosterically controls RNA binding.
A cryptic pocket in Ebola VP35 allosterically controls RNA binding.
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DOI：
10.1038/s41467-022-29927-9
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发表时间：
2022-04-27
影响因子：
16.6
通讯作者：
Bowman, Gregory R.
中科院分区：
文献类型：
--
作者：
Cruz, Matthew A.;Frederick, Thomas E.;Mallimadugula, Upasana L.;Singh, Sukrit;Vithani, Neha;Zimmerman, Maxwell, I;Porter, Justin R.;Moeder, Katelyn E.;Amarasinghe, Gaya K.;Bowman, Gregory R.
Protein-protein and protein-nucleic acid interactions are often considered difficult drug targets because the surfaces involved lack obvious druggable pockets. Cryptic pockets could present opportunities for targeting these interactions, but identifying and exploiting these pockets remains challenging. Here, we apply a general pipeline for identifying cryptic pockets to the interferon inhibitory domain (IID) of Ebola virus viral protein 35 (VP35). VP35 plays multiple essential roles in Ebola’s replication cycle but lacks pockets that present obvious utility for drug design. Using adaptive sampling simulations and machine learning algorithms, we predict VP35 harbors a cryptic pocket that is allosterically coupled to a key dsRNA-binding interface. Thiol labeling experiments corroborate the predicted pocket and mutating the predicted allosteric network supports our model of allostery. Finally, covalent modifications that mimic drug binding allosterically disrupt dsRNA binding that is essential for immune evasion. Based on these results, we expect this pipeline will be applicable to other proteins. Many viral proteins are thought to be unlikely candidates for drug discovery as they lack obvious drug binding sites. Here, the authors use computational approaches followed by experimental validation to identify a cryptic pocket within the Ebola virus protein VP35.
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DOI：
10.1073/pnas.1103629108
发表时间：
2011-06-28
影响因子：
11.1
作者：
Bernstein, Rachel;Schmidt, Kierstin L.;Marqusee, Susan
通讯作者：
Marqusee, Susan
DOI：
10.3390/ph3092838
发表时间：
2010-08-30
期刊：
Pharmaceuticals (Basel, Switzerland)
影响因子：
--
作者：
Jakubík J;El-Fakahany EE
通讯作者：
El-Fakahany EE
影响因子：
3
作者：
Duan, Y;Wu, C;Kollman, P
通讯作者：
Kollman, P
DOI：
10.1073/pnas.1417811112
发表时间：
2015-03-03
影响因子：
11.1
作者：
Bowman, Gregory R.;Bolin, Eric R.;Marqusee, Susan
通讯作者：
Marqusee, Susan
影响因子：
5.4
作者：
Cardenas, Washington B.;Loo, Yueh-Ming;Basler, Christopher F.
通讯作者：
Basler, Christopher F.