Abstract
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.
Highlights
The human immunodeficiency virus (HIV) is a well-known pandemic lentivirus responsible for millions of deaths annually worldwide, in developing and third-world countries [1]
The ultimate objective is to predict the binding mode of the CRM1-nuclear export signal (NES)-RanGTP-DDX3 protein complex and elucidate residues strongly implicated in binding between DDX3 and the CRM1 export complex
The first form contains CRM1 bound to an NES peptide as well as RanGTP while the second form is only bound to NES
Summary
The human immunodeficiency virus (HIV) is a well-known pandemic lentivirus responsible for millions of deaths annually worldwide, in developing and third-world countries [1]. Interaction of RNA Helicase DDX3 with HIV-1 Rev-CRM1-RanGTP Complex doi:10.1371/journal.pone.0112969.g001 export. HIV’s reliance on a key host protein, CRM1 ( known as XPO1 or Exportin-1), to export its unspliced and partially spliced RNA transcripts makes it a tempting target. HIV Regulator of Virion (Rev) escorts HIV-1 transcripts by recruiting CRM1 (see Fig. 1) and binding to a highly structured region present in all unspliced and partially spliced HIV transcripts, the Rev response element (RRE). Targeting the binding of CRM1 to Rev has been unsuccessful due to lack of detailed structural information [8,9]. Developing a method that interferes with viral replication at this step would be extremely valuable; before this can be considered, the binding interactions between members of the HIV-1 Rev export complex must be elucidated
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