8FNP
Structure of E138K/G140S/Q148H HIV-1 intasome with Dolutegravir bound
Summary for 8FNP
| Entry DOI | 10.2210/pdb8fnp/pdb |
| Related | 8FN7 |
| EMDB information | 29307 29321 |
| Descriptor | Lamina-associated polypeptide 2, isoform alpha,Integrase chimera, DNA (27-MER), DNA (25-MER), ... (7 entities in total) |
| Functional Keywords | integrase, nucleoprotein complex, inhibitor, drug resistance, viral protein-dna-inhibitor complex, viral protein/dna/inhibitor |
| Biological source | Homo sapiens More |
| Total number of polymer chains | 12 |
| Total formula weight | 352497.10 |
| Authors | Shan, Z.L.,Passos, D.O.,Strutzenberg, T.S.,Li, M.,Lyumkis, D. (deposition date: 2022-12-28, release date: 2023-08-09, Last modification date: 2024-06-19) |
| Primary citation | Li, M.,Oliveira Passos, D.,Shan, Z.,Smith, S.J.,Sun, Q.,Biswas, A.,Choudhuri, I.,Strutzenberg, T.S.,Haldane, A.,Deng, N.,Li, Z.,Zhao, X.Z.,Briganti, L.,Kvaratskhelia, M.,Burke Jr., T.R.,Levy, R.M.,Hughes, S.H.,Craigie, R.,Lyumkis, D. Mechanisms of HIV-1 integrase resistance to dolutegravir and potent inhibition of drug-resistant variants. Sci Adv, 9:eadg5953-eadg5953, 2023 Cited by PubMed Abstract: HIV-1 infection depends on the integration of viral DNA into host chromatin. Integration is mediated by the viral enzyme integrase and is blocked by integrase strand transfer inhibitors (INSTIs), first-line antiretroviral therapeutics widely used in the clinic. Resistance to even the best INSTIs is a problem, and the mechanisms of resistance are poorly understood. Here, we analyze combinations of the mutations E138K, G140A/S, and Q148H/K/R, which confer resistance to INSTIs. The investigational drug 4d more effectively inhibited the mutants compared with the approved drug Dolutegravir (DTG). We present 11 new cryo-EM structures of drug-resistant HIV-1 intasomes bound to DTG or 4d, with better than 3-Å resolution. These structures, complemented with free energy simulations, virology, and enzymology, explain the mechanisms of DTG resistance involving E138K + G140A/S + Q148H/K/R and show why 4d maintains potency better than DTG. These data establish a foundation for further development of INSTIs that potently inhibit resistant forms in integrase. PubMed: 37478179DOI: 10.1126/sciadv.adg5953 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (2.2 Å) |
Structure validation
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