8fly | pdb_00008fly

HIV-1 gp120 complex with BNM-III-170

spinqualitylabelsall models 8fly, resolution 2.04Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8fly is a 4 chain structure with sequence from HIV-1 06TG.HT008. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: 5VG, NAG Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed Binding to the host cell receptors, CD4 and CCR5/CXCR4, triggers large-scale conformational changes in the HIV-1 envelope glycoprotein (Env) trimer [(gp120/gp41)(3)] that promote virus entry into the cell. CD4-mimetic compounds (CD4mcs) comprise small organic molecules that bind in the highly conserved CD4-binding site of gp120 and prematurely induce inactivating Env conformational changes, including shedding of gp120 from the Env trimer. By inducing more "open," antibody-susceptible Env conformations, CD4mcs also sensitize HIV-1 virions to neutralization by antibodies and infected cells to antibody-dependent cellular cytotoxicity (ADCC). Here, we report the design, synthesis, and evaluation of novel CD4mcs based on an indoline scaffold. Compared with our current lead indane scaffold CD4mc, BNM-III-170, several indoline CD4mcs exhibit increased potency and breadth against HIV-1 variants from different geographic clades. Viruses that were selected for resistance to the lead indane CD4mc, BNM-III-170, are susceptible to inhibition by the indoline CD4mcs. The indoline CD4mcs also potently sensitize HIV-1-infected cells to ADCC mediated by plasma from HIV-1-infected individuals. Crystal structures indicate that the indoline CD4mcs gain potency compared to the indane CD4mcs through more favorable pi-pi overlap from the indoline pose and by making favorable contacts with the vestibule of the CD4-binding pocket on gp120. The rational design of indoline CD4mcs thus holds promise for further improvements in antiviral activity, potentially contributing to efforts to treat and prevent HIV-1 infection. Indoline CD4-mimetic compounds mediate potent and broad HIV-1 inhibition and sensitization to antibody-dependent cellular cytotoxicity.,Fritschi CJ, Anang S, Gong Z, Mohammadi M, Richard J, Bourassa C, Severino KT, Richter H, Yang D, Chen HC, Chiu TJ, Seaman MS, Madani N, Abrams C, Finzi A, Hendrickson WA, Sodroski JG, Smith AB 3rd Proc Natl Acad Sci U S A. 2023 Mar 28;120(13):e2222073120. doi: , 10.1073/pnas.2222073120. Epub 2023 Mar 24. PMID:36961924 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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