Structurally- and dynamically-driven allostery of the chymotrypsin-like proteases of SARS, Dengue and Zika viruses

Research output: Journal Publications and Reviews (RGC: 21, 22, 62)21_Publication in refereed journal

2 Scopus Citations
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Author(s)

  • Liangzhong Lim
  • Garvita Gupta
  • Amrita Roy
  • Jian Kang
  • Shagun Srivastava
  • Jianxing Song

Related Research Unit(s)

Detail(s)

Original languageEnglish
Pages (from-to)52-66
Journal / PublicationProgress in Biophysics and Molecular Biology
Volume143
Online published11 Sep 2018
Publication statusPublished - May 2019

Abstract

Coronavirus 3C-like and Flavivirus NS2B-NS3 proteases utilize the chymotrypsin fold to harbor their catalytic machineries but also contain additional domains/co-factors. Over the past decade, we aimed to decipher how the extra domains/co-factors mediate the catalytic machineries of SARS 3C-like, Dengue and Zika NS2B-NS3 proteases by characterizing their folding, structures, dynamics and inhibition with NMR, X-ray crystallography and MD simulations, and the results revealed: 1)the chymotrypsin fold of the SARS 3C-like protease can independently fold, while, by contrast, those of Dengue and Zika proteases lack the intrinsic capacity to fold without co-factors. 2)Mutations on the extra domain of SARS 3C-like protease can transform the active catalytic machinery into the inactive collapsed state by structurally-driven allostery. 3)Amazingly, even without detectable structural changes, mutations on the extra domain are sufficient to either inactivate or enhance the catalytic machinery of SARS 3C-like protease by dynamically-driven allostery. 4)Global networks of correlated motions have been identified: for SARS 3C-like protease, N214A inactivates the catalytic machinery by decoupling the network, while STI/A and STIF/A enhance by altering the patterns of the network. The global networks of Dengue and Zika proteases are coordinated by their NS2B-cofactors. 5)Natural products were identified to allosterically inhibit Zika and Dengue proteases through binding a pocket on the back of the active site. Therefore, by introducing extra domains/cofactors, nature develops diverse strategies to regulate the catalytic machinery embedded on the chymotrypsin fold through folding, structurally- and dynamically-driven allostery, all of which might be exploited to develop antiviral drugs.

Research Area(s)

  • 3C-like protease, Chymotrypsin fold, Correlated motions, Enzymatic allostery, Flavivirus, Natural product, NS2B-NS3 protease, SARS coronavirus

Citation Format(s)

Structurally- and dynamically-driven allostery of the chymotrypsin-like proteases of SARS, Dengue and Zika viruses. / Lim, Liangzhong; Gupta, Garvita; Roy, Amrita; Kang, Jian; Srivastava, Shagun; Shi, Jiahai; Song, Jianxing.

In: Progress in Biophysics and Molecular Biology, Vol. 143, 05.2019, p. 52-66.

Research output: Journal Publications and Reviews (RGC: 21, 22, 62)21_Publication in refereed journal