6dh2 | pdb_00006dh2

Crystal structure of HIV-1 Protease NL4-3 I84V Mutant in complex with UMass6

spinqualitylabelsall models 6dh2, resolution 1.98Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6dh2 is a 2 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: A60, SO4 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed HIV-1 protease is one of the prime targets of agents used in antiretroviral therapy against HIV. However, under selective pressure of protease inhibitors, primary mutations at the active site weaken inhibitor binding to confer resistance. Darunavir (DRV) is the most potent HIV-1 protease inhibitor in clinic; resistance is limited, as DRV fits well within the substrate envelope. Nevertheless, resistance is observed due to hydrophobic changes at residues including I50, V82 and I84 that line the S1/S1' pocket within the active site. Through enzyme inhibition assays and a series of 12 crystal structures, we interrogated susceptibility of DRV and two potent analogs to primary S1' mutations. The analogs had modifications at the hydrophobic P1' moiety compared to DRV to better occupy the unexploited space in the S1' pocket where the primary mutations were located. Considerable losses of potency were observed against protease variants with I84V and I50V mutations for all three inhibitors. The crystal structures revealed an unexpected conformational change in the flap region of I50V protease bound to the analog with the largest P1' moiety, indicating interdependency between the S1' subsite and the flap region. Collective analysis of protease-inhibitor interactions in the crystal structures using principle component analysis was able to distinguish inhibitor identity and relative potency solely based on vdW contacts. Our results reveal the complexity of the interplay between inhibitor P1' moiety and S1' mutations, and validate principle component analyses as a useful tool for distinguishing resistance and inhibitor potency. Structural Adaptation of Darunavir Analogs Against Primary Mutations in HIV-1 Protease.,Lockbaum GJ, Leidner F, Rusere LN, Henes M, Kosovrasti K, Nachum GS, Nalivaika EA, Ali A, Kurt Yilmaz N, Schiffer CA ACS Infect Dis. 2018 Dec 13. doi: 10.1021/acsinfecdis.8b00336. PMID:30543749 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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