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Journal of Virology, September 2007, p. 9512-9518, Vol. 81, No. 17
0022-538X/07/$08.00+0     doi:10.1128/JVI.00799-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Crystal Structure of Lysine Sulfonamide Inhibitor Reveals the Displacement of the Conserved Flap Water Molecule in Human Immunodeficiency Virus Type 1 Protease{triangledown}

Madhavi N. L. Nalam,1 Anik Peeters,2 Tim H. M. Jonckers,2 Inge Dierynck,2 and Celia A. Schiffer1*

Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts 01605,1 Tibotec BVBA, Generaal de Wittelaan L 11B 3, B-2800 Mechelen, Belgium2

Received 13 April 2007/ Accepted 14 June 2007

Human immunodeficiency virus type 1 (HIV-1) protease has been continuously evolving and developing resistance to all of the protease inhibitors. This requires the development of new inhibitors that bind to the protease in a novel fashion. Most of the inhibitors that are on the market are peptidomimetics, where a conserved water molecule mediates hydrogen bonding interactions between the inhibitors and the flaps of the protease. Recently a new class of inhibitors, lysine sulfonamides, was developed to combat the resistant variants of HIV protease. Here we report the crystal structure of a lysine sulfonamide. This inhibitor binds to the active site of HIV-1 protease in a novel manner, displacing the conserved water and making extensive hydrogen bonds with every region of the active site.

* Corresponding author. Mailing address: Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, 364 Plantation Street, Worcester, MA 01605. Phone: (508) 856-8008. Fax: (508) 856-6464. E-mail: celia.schiffer{at}umassmed.edu

{triangledown} Published ahead of print on 27 June 2007.

Journal of Virology, September 2007, p. 9512-9518, Vol. 81, No. 17
0022-538X/07/$08.00+0     doi:10.1128/JVI.00799-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.





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