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Nature Structural Biology  2, 274 - 280 (1995)

Flexibility and function in HIV-1 protease

Linda K. Nicholson1, Toshimasa Yamazaki1, Dennis A. Torchia1, Stephan Grzesiek2, Ad Bax2, Stephen J. Stahl3, Joshua D. Kaufman3, Paul T. Wingfield3, Patrick Y.S Lam4, Prabhakar K. Jadhav4, C. Nicholas Hodge4, Peter J. Domaille4 & Chong-Hwan Chang4

  1Molecular Structural Biology Unit, National Institute of Dental Research, Bethesda, Maryland 20892 USA

  2Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland 20892 USA

  3Protein Expression Laboratory, Office of the Director, National Institutes of Health, Bethesda, Maryland 20892 USA

  4Department of Chemical and Physical Sciences, The DuPont Merck Pharmaceutical Company, Wilmington, Delaware 19880-0400 USA

HIV protease is a homodimeric protein whose activity is essential to viral function. We have investigated the molecular dynamics of the HIV protease, thought to be important for proteinase function, bound to high affinity inhibitors using NMR techniques. Analysis of 15N spin relaxation parameters, of all but 13 backbone amide sites, reveals the presence of significant internal motions of the protein backbone. In particular, the flaps that cover the proteins active site of the protein have terminal loops that undergo large amplitude motions on the ps to ns time scale, while the tips of the flaps undergo a conformational exchange on the mus time scale. This enforces the idea that the flaps of the proteinase are flexible structures that facilitate function by permitting substrate access to and product release from the active site of the enzyme.

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