5E5K

Joint X-ray/neutron structure of HIV-1 protease triple mutant (V32I,I47V,V82I) with darunavir at pH 4.3

Summary for 5E5K

• Entry DOI: 10.2210/pdb5e5k/pdb
• Descriptor: HIV-1 protease, (3R,3AS,6AR)-HEXAHYDROFURO[2,3-B]FURAN-3-YL(1S,2R)-3-[[(4-AMINOPHENYL)SULFONYL](ISOBUTYL)AMINO]-1-BENZYL-2-HYDROXYPROPYLCARBAMATE (3 entities in total)
• Functional Keywords: protease drug resistant mutant inhibitor complex, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Human immunodeficiency virus type 1 group M subtype B (HIV-1)
• Total number of polymer chains: 2
• Total formula weight: 22057.07

Authors

Kovalevsky, A.Y.,Das, A. (deposition date: 2015-10-08, release date: 2016-05-04, Last modification date: 2024-03-06)

Primary citation

Gerlits, O.,Wymore, T.,Das, A.,Shen, C.H.,Parks, J.M.,Smith, J.C.,Weiss, K.L.,Keen, D.A.,Blakeley, M.P.,Louis, J.M.,Langan, P.,Weber, I.T.,Kovalevsky, A.
Long-Range Electrostatics-Induced Two-Proton Transfer Captured by Neutron Crystallography in an Enzyme Catalytic Site.
Angew.Chem.Int.Ed.Engl., 55:4924-4927, 2016

PubMed Abstract: Neutron crystallography was used to directly locate two protons before and after a pH-induced two-proton transfer between catalytic aspartic acid residues and the hydroxy group of the bound clinical drug darunavir, located in the catalytic site of enzyme HIV-1 protease. The two-proton transfer is triggered by electrostatic effects arising from protonation state changes of surface residues far from the active site. The mechanism and pH effect are supported by quantum mechanics/molecular mechanics (QM/MM) calculations. The low-pH proton configuration in the catalytic site is deemed critical for the catalytic action of this enzyme and may apply more generally to other aspartic proteases. Neutrons therefore represent a superb probe to obtain structural details for proton transfer reactions in biological systems at a truly atomic level.

PubMed: 26958828
DOI: 10.1002/anie.201509989

Experimental method

NEUTRON DIFFRACTION (2.3 Å)
X-RAY DIFFRACTION (1.75 Å)