8DCI
Crystal Structure of a highly resistant HIV-1 protease Clinical isolate PR10x (inhibitor-free)
Summary for 8DCI
| Entry DOI | 10.2210/pdb8dci/pdb |
| Related | 3PWM 3PWR 6DIL 6DJ2 6DJ5 8DCH |
| Descriptor | Protease (2 entities in total) |
| Functional Keywords | hiv/aids, hiv protease, drug resistant clinical mutant, evolution of drug resistance, distal mutations, viral protein, hydrolase |
| Biological source | Human immunodeficiency virus 1 |
| Total number of polymer chains | 2 |
| Total formula weight | 21569.12 |
| Authors | Wong-Sam, A.E.,Wang, Y.-F.,Weber, I.T. (deposition date: 2022-06-16, release date: 2022-10-05, Last modification date: 2023-10-18) |
| Primary citation | Wong-Sam, A.,Wang, Y.F.,Kneller, D.W.,Kovalevsky, A.Y.,Ghosh, A.K.,Harrison, R.W.,Weber, I.T. HIV-1 protease with 10 lopinavir and darunavir resistance mutations exhibits altered inhibition, structural rearrangements and extreme dynamics. J.Mol.Graph.Model., 117:108315-108315, 2022 Cited by PubMed Abstract: Antiretroviral drug resistance is a therapeutic obstacle for people with HIV. HIV protease inhibitors darunavir and lopinavir are recommended for resistant infections. We characterized a protease mutant (PR10x) derived from a highly resistant clinical isolate including 10 mutations associated with resistance to lopinavir and darunavir. Compared to the wild-type protease, PR10x exhibits ∼3-fold decrease in catalytic efficiency and K values of 2-3 orders of magnitude worse for darunavir, lopinavir, and potent investigational inhibitor GRL-519. Crystal structures of the mutant were solved in a ligand-free form and in complex with GRL-519. The structures show altered interactions in the active site, flap-core interface, hydrophobic core, hinge region, and 80s loop compared to the corresponding wild-type protease structures. The ligand-free crystal structure exhibits a highly curled flap conformation which may amplify drug resistance. Molecular dynamics simulations performed for 1 μs on ligand-free dimers showed extremely large fluctuations in the flaps for PR10x compared to equivalent simulations on PR with a single L76V mutation or wild-type protease. This analysis offers insight about the synergistic effects of mutations in highly resistant variants. PubMed: 36108568DOI: 10.1016/j.jmgm.2022.108315 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.62 Å) |
Structure validation
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