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Structural and Functional Analysis of HIV-1 Coreceptors: Roles of Charged Residues and Posttranslational Modifications on Coreceptor Activity

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Technical Report

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Uniformed Services University Of The Health Sciences Bethesda United States

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CXCR4 and CCR5 are chemokine receptors and are coreceptors for human immunodeficiency virus HIV-1. Host cells must express CD4 and a coreceptor for optimal HIV-1 entry. The delineation of the critical regions involved in the interactions within the Env-CD4-coreceptor complex has been under intensive investigation. To define these regions we have employed an alanine-scanning mutagenesis strategy of the extracellular domains of CXCR4 coupled with a highly sensitive reporter-gene assay for HIV-1 Env-mediated membrane fusion. Using a panel of 47 different CXCR4 mutations, we have identified several charged residues that appear important for coreceptor activity for X4 Envs mutations E15A and E32A in the N-terminus, D97A in extracellular loopecl-1, and R188A in ecl-2 impaired coreceptor activity for X4 and R5X4 Envs. Mutation to alanine of one of the six tyrosines present in CXCR4, Y7, decreased coreceptor function. In addition, alanine substitution of any of the four extracellular cysteines alone resulted in conformational changes of varying degrees, while paired cysteine deletions could partially retain structure. Our data supports the notion that all four cysteines are involved in disulfide bond formation.

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