Dynamics of "flap" structures in three HIV-1 protease/inhibitor complexes probed by total chemical synthesis and pulse-EPR spectroscopy

Vladimir Yu Torbeev; H Raghuraman; Kalyaneswar Mandal; Sanjib Senapati; Eduardo Perozo; Stephen B H Kent

doi:10.1021/ja806526z

Dynamics of "flap" structures in three HIV-1 protease/inhibitor complexes probed by total chemical synthesis and pulse-EPR spectroscopy

J Am Chem Soc. 2009 Jan 28;131(3):884-5. doi: 10.1021/ja806526z.

Authors

Vladimir Yu Torbeev¹, H Raghuraman, Kalyaneswar Mandal, Sanjib Senapati, Eduardo Perozo, Stephen B H Kent

Affiliation

¹ Institute for Biophysical Dynamics, Department of Chemistry, The University of Chicago, Chicago, Illinois 60637, USA.

PMID: 19117390
DOI: 10.1021/ja806526z

Abstract

The unliganded form of nitroxide spin-labeled HIV-1 protease and three different complexes with inhibitors were studied by pulse-EPR spectroscopy to determine "interflap" distance distributions in solution. In the unliganded enzyme, we observed a rather broad distribution with three maxima corresponding to three flap conformers; the principal form is a "semiopen/semiopen" conformer. In the complexes with inhibitors, the dominant conformer is an asymmetric "closed/semiopen" form. Moreover, the distance distribution profile is significantly varied among the different inhibitors, which mimic different species on the reaction coordinate for enzyme catalyzed proteolysis.

Publication types

Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Electron Spin Resonance Spectroscopy
HIV Protease / chemistry*
HIV Protease / metabolism
HIV Protease Inhibitors / chemical synthesis*
HIV Protease Inhibitors / chemistry
Models, Molecular
Protein Structure, Tertiary

Substances

HIV Protease Inhibitors
HIV Protease
p16 protease, Human immunodeficiency virus 1