6MU7

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

Summary for 6MU7

• Entry DOI: 10.2210/pdb6mu7/pdb
• Descriptor: Envelope glycoprotein gp160, alpha-D-mannopyranose-(1-2)-alpha-D-mannopyranose-(1-2)-alpha-D-mannopyranose-(1-3)-[alpha-D-mannopyranose-(1-2)-alpha-D-mannopyranose-(1-6)-[alpha-D-mannopyranose-(1-3)]alpha-D-mannopyranose-(1-6)]beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, 2-acetamido-2-deoxy-beta-D-glucopyranose, ... (13 entities in total)
• Functional Keywords: hiv-1 envelope prefusion trimer, entry inhibitors, immune system-inhibitor complex, immune system/inhibitor
• Biological source: Human immunodeficiency virus 1; More
• Total number of polymer chains: 6
• Total formula weight: 156329.20

Authors

Lai, Y.-T.,Kwong, P.D. (deposition date: 2018-10-22, release date: 2019-01-16, Last modification date: 2024-10-23)

Primary citation

Lai, Y.T.,Wang, T.,O'Dell, S.,Louder, M.K.,Schon, A.,Cheung, C.S.F.,Chuang, G.Y.,Druz, A.,Lin, B.,McKee, K.,Peng, D.,Yang, Y.,Zhang, B.,Herschhorn, A.,Sodroski, J.,Bailer, R.T.,Doria-Rose, N.A.,Mascola, J.R.,Langley, D.R.,Kwong, P.D.
Lattice engineering enables definition of molecular features allowing for potent small-molecule inhibition of HIV-1 entry.
Nat Commun, 10:47-47, 2019

PubMed Abstract: 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 β20-β21 hairpin to improve potency.

PubMed: 30604750
DOI: 10.1038/s41467-018-07851-1

Experimental method

X-RAY DIFFRACTION (2.501 Å)