4OBG
Crystal Structure of Nelfinavir-Resistant, Inactive HIV-1 Protease (D30N/N88D) in Complex with the p1-p6 substrate.
Summary for 4OBG
| Entry DOI | 10.2210/pdb4obg/pdb |
| Related | 4OBD 4OBF 4OBH 4OBJ 4OBK |
| Descriptor | HIV-1 Protease, p1-p6 peptide, GLYCEROL, ... (6 entities in total) |
| Functional Keywords | co-evolution, resistance, hydrolase |
| Biological source | Human immunodeficiency virus type 1 (HIV-1) More |
| Cellular location | Gag-Pol polyprotein: Host cell membrane; Lipid-anchor. Matrix protein p17: Virion membrane; Lipid- anchor . Capsid protein p24: Virion . Nucleocapsid protein p7: Virion . Reverse transcriptase/ribonuclease H: Virion . Integrase: Virion : P03369 Gag polyprotein: Host cell membrane ; Lipid-anchor . Matrix protein p17: Virion membrane ; Lipid-anchor . Capsid protein p24: Virion . Nucleocapsid protein p7: Virion : P03349 |
| Total number of polymer chains | 6 |
| Total formula weight | 46598.66 |
| Authors | Kolli, M. (deposition date: 2014-01-07, release date: 2014-11-26, Last modification date: 2023-09-20) |
| Primary citation | Kolli, M.,Ozen, A.,Kurt-Yilmaz, N.,Schiffer, C.A. HIV-1 protease-substrate coevolution in nelfinavir resistance. J.Virol., 88:7145-7154, 2014 Cited by PubMed Abstract: Resistance to various human immunodeficiency virus type 1 (HIV-1) protease inhibitors (PIs) challenges the effectiveness of therapies in treating HIV-1-infected individuals and AIDS patients. The virus accumulates mutations within the protease (PR) that render the PIs less potent. Occasionally, Gag sequences also coevolve with mutations at PR cleavage sites contributing to drug resistance. In this study, we investigated the structural basis of coevolution of the p1-p6 cleavage site with the nelfinavir (NFV) resistance D30N/N88D protease mutations by determining crystal structures of wild-type and NFV-resistant HIV-1 protease in complex with p1-p6 substrate peptide variants with L449F and/or S451N. Alterations of residue 30's interaction with the substrate are compensated by the coevolving L449F and S451N cleavage site mutations. This interdependency in the PR-p1-p6 interactions enhances intermolecular contacts and reinforces the overall fit of the substrate within the substrate envelope, likely enabling coevolution to sustain substrate recognition and cleavage in the presence of PR resistance mutations. PubMed: 24719428DOI: 10.1128/JVI.00266-14 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.78 Å) |
Structure validation
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