Download MendeleyLattice engineering enables definition of molecular features allowing for potent small-molecule inhibition of HIV-1 entry.
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.(2019) Nat Commun 10: 47-47
- PubMed: 30604750
- DOI: https://doi.org/10.1038/s41467-018-07851-1
- Primary Citation of Related Structures:
6MTJ, 6MTN, 6MU6, 6MU7, 6MU8, 6MUF, 6MUG - 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.
Organizational Affiliation:
Vaccine Research Center, NIAID, National Institutes of Health, Bethesda, MD, 20892, USA.
