Virion with exposed coreceptor binding sites CCR5/CXCR4 Virion with CD4:gp120 bound to CCR5/CXCR4 CD4:gp120 binds to chemokine co-receptor CCR5/CXCR4 Authored: Morrow, MP, Bukrinsky, M, 2006-03-07 21:26:47 Edited: Gopinathrao, G, 2006-02-17 18:35:46 Once the viral gp120 protein has bound to cellular CD4, its bridging sheet region becomes exposed/formed as a result of conformation changes in the V1 and V2 loops as well as a conformational change in the gp120 core domain. Once this region is exposed, it is free to bind the HIV co-receptors CCR5 or CXCR4 (also known as chemokine receptors). Different viruses use different co-receptors (CCR5 or CXCR4) for entry, and many studies investigated the structural determinants of interaction between gp120 and the co-receptor. <br>Studies of CCR5 binding by gp120 revealed that active regions in the second extracellular loop (ECL2), the N-terminal extracellular domain (specifically the NYYTSE motif) and at the junction between the fifth transmembrane domain and third cytoplasmic loop of the receptor are important for viral attachment and subsequent fusion. The N-terminal region likely interacts with the core of gp120 (bridging sheet and adjacent regions) and the base of V3, while ECL2 may be important for interacting with the tip of V3. The transmembrane 5 / cytoplasmic loop 3 junction of CCR5 has been shown to influence the conformation of the receptor which allows for subsequent binding of gp120 (Wang et al.,1999). Deletion of the V3 loop in gp120 abolished Env interaction with co-receptor without affecting the binding of soluble gp120 to CD4, underscoring the importance of this loop in chemokine receptor, but not CD4, binding. Furthermore, the V3 loop is a major determinant of coreceptor specificity, with amino acid at positions 11 and 25 being partly predictive of CCR5 or CXCR4 use. Single amino acid changes in V3 can alter coreceptor use, however sequences outside of V3 can also contribute to coreceptor specificity. <br> Pubmed10497202 Pubmed16284180 Pubmed8649511 Pubmed8658171 Pubmed8674119 Pubmed8906796 Pubmed9311827 Pubmed9499113 Pubmed9632396 Pubmed9641677 Pubmed9721247 Reactome Database ID Release 43164507 Reactome, http://www.reactome.org ReactomeREACT_7962 Reviewed: Reeves, J, 2006-06-12 15:22:40