3el4

Crystal structure of inhibitor saquinavir (SQV) complexed with the multidrug HIV-1 protease variant L63P/V82T/I84VCrystal structure of inhibitor saquinavir (SQV) complexed with the multidrug HIV-1 protease variant L63P/V82T/I84V

Structural highlights 3el4 is a 2 chain structure with sequence from Hiv-1 m:b_arv2/sf2. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: , Related: 3ekp, 3ekq, 3ekt, 3ekv, 3ekw, 3ekx, 3eky, 3el0, 3el5, 3em3, 3em4, 3em6 Gene: gag-pol (HIV-1 M:B_ARV2/SF2) Activity: HIV-1 retropepsin, with EC number 3.4.23.16 Resources: FirstGlance, OCA, RCSB, PDBsum Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMed The development of HIV-1 protease inhibitors has been the historic paradigm of rational structure-based drug design, where structural and thermodynamic analyses have assisted in the discovery of novel inhibitors. While the total enthalpy and entropy change upon binding determine the affinity, often the thermodynamics are considered in terms of inhibitor properties only. In the current study, profound changes are observed in the binding thermodynamics of a drug-resistant variant compared to wild-type HIV-1 protease, irrespective of the inhibitor bound. This variant (Flap+) has a combination of flap and active site mutations and exhibits extremely large entropy-enthalpy compensation compared to wild-type protease, 5-15 kcal/mol, while losing only 1-3 kcal/mol in total binding free energy for any of six FDA-approved inhibitors. Although entropy-enthalpy compensation has been previously observed for a variety of systems, never have changes of this magnitude been reported. The co-crystal structures of Flap+ protease with four of the inhibitors were determined and compared with complexes of both the wild-type protease and another drug-resistant variant that does not exhibit this energetic compensation. Structural changes conserved across the Flap+ complexes, which are more pronounced for the flaps covering the active site, likely contribute to the thermodynamic compensation. The finding that drug-resistant mutations can profoundly modulate the relative thermodynamic properties of a therapeutic target independent of the inhibitor presents a new challenge for rational drug design. Extreme Entropy-Enthalpy Compensation in a Drug-Resistant Variant of HIV-1 Protease.,King NM, Prabu-Jeyabalan M, Bandaranayake RM, Nalam MN, Nalivaika EA, Ozen A, Haliloglu T, Yilmaz NK, Schiffer CA ACS Chem Biol. 2012 Jul 2. PMID:22712830 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Virus protease

spinqualitylabelsall models 3el4, resolution 2.00Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image