Molecular recognition of CCR5 by an HIV-1 gp120 V3 loop.
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.
Department of Chemical and Biological Engineering, Princeton University, Princeton, New Jersey, United States of America.
Phanourios
P
Tamamis
Department of Chemical and Biological Engineering, Princeton University, Princeton, New Jersey, United States of America.
Christodoulos A
CA
Floudas
D020816:Amino Acid Motifs; D003510:Cyclohexanes / Q000737:chemistry; D015699:HIV Envelope Protein gp120 / Q000737:chemistry*; D023581:HIV Fusion Inhibitors / Q000737:chemistry; D015497:HIV-1; D006801:Humans; D006860:Hydrogen Bonding; D000077592:Maraviroc; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D017433:Protein Structure, Secondary; D019713:Receptors, CCR5 / Q000737:chemistry*; D019718:Receptors, CXCR4 / Q000737:chemistry; D013816:Thermodynamics; D014230:Triazoles / Q000737:chemistry
C584933:CCR5 protein, human; C527276:CXCR4 protein, human; D003510:Cyclohexanes; D015699:HIV Envelope Protein gp120; D023581:HIV Fusion Inhibitors; D019713:Receptors, CCR5; D019718:Receptors, CXCR4; D014230:Triazoles; D000077592:Maraviroc