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Title: The interaction of RNA helicase DDX3 with HIV-1 Rev-CRM1-RanGTP complex during the HIV replication cycle

Journal Article · · PLoS ONE
 [1];  [1];  [2]
  1. Univ. of California, Berkeley, CA (United States). Molecular Cell Biomechanics Lab.
  2. Univ. of California, Berkeley, CA (United States). Molecular Cell Biomechanics Lab.; Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
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Molecular traffic between the nucleus and the cytoplasm is regulated by the nuclear pore complex (NPC), which acts as a highly selective channel perforating the nuclear envelope in eukaryotic cells. The human immunodeficiency virus (HIV) exploits the nucleocytoplasmic pathway to export its RNA transcripts across the NPC to the cytoplasm. Despite extensive study on the HIV life cycle and the many drugs developed to target this cycle, no current drugs have been successful in targeting the critical process of viral nuclear export, even though HIV’s reliance on a single host protein, CRM1, to export its unspliced and partially spliced RNA transcripts makes it a tempting target. Due to recent findings implicating a DEAD-box helicase, DDX3, in HIV replication and a member of the export complex, it has become an appealing target for anti-HIV drug inhibition. In the present research, we have applied a hybrid computational protocol to analyze protein-protein interactions in the HIV mRNA export cycle. This method is based on molecular docking followed by molecular dynamics simulation and accompanied by approximate free energy calculation (MM/GBSA), computational alanine scanning, clustering, and evolutionary analysis. We highlight here some of the most likely binding modes and interfacial residues between DDX3 and CRM1 both in the absence and presence of RanGTP. This work shows that although DDX3 can bind to free CRM1, addition of RanGTP leads to more concentrated distribution of binding modes and stronger binding between CRM1 and RanGTP.

Research Organization:
Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)
Sponsoring Organization:
USDOE
Grant/Contract Number:
AC02-05CH11231
OSTI ID:
1188325
Journal Information:
PLoS ONE, Vol. 10, Issue 2; ISSN 1932-6203
Publisher:
Public Library of ScienceCopyright Statement
Country of Publication:
United States
Language:
English
Citation Metrics:
Cited by: 22 works
Citation information provided by
Web of Science

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Cited By (9)

Insight into the structural stability of coumestrol with human estrogen receptor α and β subtypes: a combined approach involving docking and molecular dynamics simulation studies journal January 2015
Focus on Translation Initiation of the HIV-1 mRNAs journal December 2018
Exportin-1-Dependent Nuclear Export of DEAD-box Helicase DDX3X is Central to its Role in Antiviral Immunity journal September 2019
Nuclear DDX3 expression predicts poor outcome in colorectal and breast cancer journal July 2017
The RNA helicase DDX3X is an essential mediator of innate antimicrobial immunity journal November 2018
The Effect of Cell Morphology on the Permeability of the Nuclear Envelope to Diffusive Factors journal July 2018
Antitumor effect of proanthocyanidin induced apoptosis in human colorectal cancer (HT-29) cells and its molecular docking studies journal February 2019
SCRIBER: accurate and partner type-specific prediction of protein-binding residues from proteins sequences journal July 2019
Constructing an integrated genetic and epigenetic cellular network for whole cellular mechanism using high-throughput next-generation sequencing data journal February 2016

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59 BASIC BIOLOGICAL SCIENCES