6mu7

From Proteopedia

Crystal Structure of HIV-1 BG505 SOSIP.664 Prefusion Env Trimer Bound to Small Molecule HIV-1 Entry Inhibitor BMS-818251 in Complex with Human Antibodies 3H109L and 35O22 at 3.1 Angstrom

Structural highlights

6mu7 is a 6 chain structure with sequence from Homo sapiens and Human immunodeficiency virus 1. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.501Å
Ligands:	, , ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

Q2N0S6_9HIV1 The envelope glyprotein gp160 precursor down-modulates cell surface CD4 antigen by interacting with it in the endoplasmic reticulum and blocking its transport to the cell surface (By similarity).[RuleBase:RU004292][SAAS:SAAS000328_004_020447] The gp120-gp41 heterodimer allows rapid transcytosis of the virus through CD4 negative cells such as simple epithelial monolayers of the intestinal, rectal and endocervical epithelial barriers. Both gp120 and gp41 specifically recognize glycosphingolipids galactosyl-ceramide (GalCer) or 3' sulfo-galactosyl-ceramide (GalS) present in the lipid rafts structures of epithelial cells. Binding to these alternative receptors allows the rapid transcytosis of the virus through the epithelial cells. This transcytotic vesicle-mediated transport of virions from the apical side to the basolateral side of the epithelial cells does not involve infection of the cells themselves (By similarity).[SAAS:SAAS000328_004_240990]

Publication Abstract from PubMed

Diverse entry inhibitors targeting the gp120 subunit of the HIV-1 envelope (Env) trimer have been developed including BMS-626529, also called temsavir, a prodrug version of which is currently in phase III clinical trials. Here we report the characterization of a panel of small-molecule inhibitors including BMS-818251, which we show to be >10-fold more potent than temsavir on a cross-clade panel of 208-HIV-1 strains, as well as the engineering of a crystal lattice to enable structure determination of the interaction between these inhibitors and the HIV-1 Env trimer at higher resolution. By altering crystallization lattice chaperones, we identify a lattice with both improved diffraction and robust co-crystallization of HIV-1 Env trimers from different clades complexed to entry inhibitors with a range of binding affinities. The improved diffraction reveals BMS-818251 to utilize functional groups that interact with gp120 residues from the conserved beta20-beta21 hairpin to improve potency.

Lattice engineering enables definition of molecular features allowing for potent small-molecule inhibition of HIV-1 entry.,Lai YT, Wang T, O'Dell S, Louder MK, Schon A, Cheung CSF, Chuang GY, Druz A, Lin B, McKee K, Peng D, Yang Y, Zhang B, Herschhorn A, Sodroski J, Bailer RT, Doria-Rose NA, Mascola JR, Langley DR, Kwong PD Nat Commun. 2019 Jan 3;10(1):47. doi: 10.1038/s41467-018-07851-1. PMID:30604750^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Lai YT, Wang T, O'Dell S, Louder MK, Schon A, Cheung CSF, Chuang GY, Druz A, Lin B, McKee K, Peng D, Yang Y, Zhang B, Herschhorn A, Sodroski J, Bailer RT, Doria-Rose NA, Mascola JR, Langley DR, Kwong PD. Lattice engineering enables definition of molecular features allowing for potent small-molecule inhibition of HIV-1 entry. Nat Commun. 2019 Jan 3;10(1):47. doi: 10.1038/s41467-018-07851-1. PMID:30604750 doi:http://dx.doi.org/10.1038/s41467-018-07851-1