3EKV

Crystal structure of the wild type HIV-1 protease with the inhibitor, Amprenavir

Summary for 3EKV

• Entry DOI: 10.2210/pdb3ekv/pdb
• Related: 3EKP 3EKQ 3EKT 3EKW 3EKX 3EKY 3EL0 3EL1 3EL4 3EL5
• Descriptor: Protease, {3-[(4-AMINO-BENZENESULFONYL)-ISOBUTYL-AMINO]-1-BENZYL-2-HYDROXY-PROPYL}-CARBAMIC ACID TETRAHYDRO-FURAN-3-YL ESTER, ACETATE ION, ... (4 entities in total)
• Functional Keywords: protease inhibitor, drug resistance, amprenavir, hiv protease, aids, protease, hydrolase
• Biological source: HIV-1 M:B_ARV2/SF2 (HIV-1)
• 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
• Total number of polymer chains: 2
• Total formula weight: 22373.38

Authors

Schiffer, C.A.,Nalam, M.N.L. (deposition date: 2008-09-19, release date: 2009-09-01, Last modification date: 2023-08-30)

Primary citation

King, N.M.,Prabu-Jeyabalan, M.,Bandaranayake, R.M.,Nalam, M.N.,Nalivaika, E.A.,Ozen, A.,Yilmaz, N.K.,Schiffer, C.A.
Extreme Entropy-Enthalpy Compensation in a Drug-Resistant Variant of HIV-1 Protease.
Acs Chem.Biol., 7:1536-1546, 2012

PubMed Abstract: 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.

PubMed: 22712830
DOI: 10.1021/cb300191k

Experimental method

X-RAY DIFFRACTION (1.75 Å)