Abstract
The binding of protein HIV-1 gp120 to coreceptors CCR5 or CXCR4 is a key step of the HIV-1 entry to the host cell, and is predominantly mediated through the V3 loop fragment of HIV-1 gp120. In the present work, we delineate the molecular recognition of chemokine receptor CCR5 by a dual tropic HIV-1 gp120 V3 loop, using a comprehensive set of computational tools predominantly based on molecular dynamics simulations and free energy calculations. We report, what is to our knowledge, the first complete HIV-1 gp120 V3 loop : CCR5 complex structure, which includes the whole V3 loop and the N-terminus of CCR5, and exhibits exceptional agreement with previous experimental findings. The computationally derived structure sheds light into the functional role of HIV-1 gp120 V3 loop and CCR5 residues associated with the HIV-1 coreceptor activity, and provides insights into the HIV-1 coreceptor selectivity and the blocking mechanism of HIV-1 gp120 by maraviroc. By comparing the binding of the specific dual tropic HIV-1 gp120 V3 loop with CCR5 and CXCR4, we observe that the HIV-1 gp120 V3 loop residues 13–21, which include the tip, share nearly identical structural and energetic properties in complex with both coreceptors. This result paves the way for the design of dual CCR5/CXCR4 targeted peptides as novel potential anti-AIDS therapeutics.
Highlights
The first step of the Human Immunodeficiency Virus type 1 (HIV-1) cell entry comprises the interaction of the envelope glycoprotein gp120 with the host leukocyte glycoprotein receptor, CD4, and the binding to chemokine receptors CCR5 or CXCR4 [1,2,3,4,5,6,7,8]
Owing to the remarkable agreement of the derived structure with previous experimental findings, the computationally derived structure elucidated the key interactions between the HIV-1 gp120 V3 loop and CXCR4 which are associated with the HIV-1 coreceptor activity [30]
What is to our knowledge, the first complete HIV-1 gp120 V3 loop : CCR5 structure which is in exceptional agreement with experiments
Summary
The first step of the Human Immunodeficiency Virus type 1 (HIV-1) cell entry comprises the interaction of the envelope glycoprotein gp120 with the host leukocyte glycoprotein receptor, CD4, and the binding to chemokine receptors CCR5 or CXCR4 [1,2,3,4,5,6,7,8]. As a result of the interaction of glycoprotein gp120 with CD4, the third variable region (V3) loop of gp120 is exposed [9], and subsequently, it binds to chemokine receptors CCR5 or CXCR4, infecting mostly CD4+ T-cells [1,2]. Upon the V3 loop-coreceptor binding, a series of rearrangements in the envelope glycoproteins occur which lead to the fusion of the host and virus cell membranes [3,4]. Owing to the remarkable agreement of the derived structure with previous experimental findings, the computationally derived structure elucidated the key interactions between the HIV-1 gp120 V3 loop and CXCR4 which are associated with the HIV-1 coreceptor activity [30]
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