Crystal structure of the HIV-1 integrase core domain in complex with sucrose reveals details of an allosteric inhibitory binding site

Wielens, Jerome; Headey, Stephen J.; Jeevarajah, Dharshini; Rhodes, David I.; Deadman, John; Chalmers, David K.; Scanlon, Martin J.; Parker, Michael W.

doi:10.1016/j.febslet.2010.03.016

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Volume 584, Issue 8 , Pages 1455-1462, 16 April 2010

Crystal structure of the HIV-1 integrase core domain in complex with sucrose reveals details of an allosteric inhibitory binding site

Edited by Hans Eklund

Jerome Wielens
- Medicinal Chemistry and Drug Action, Monash Institute of Pharmaceutical Sciences, 381 Royal Parade, Parkville, Victoria 3052, Australia
- Structural Biology Laboratory, St. Vincent’s Institute, 9 Princes Street, Fitzroy, Victoria 3065, Australia
Stephen J. Headey
- Medicinal Chemistry and Drug Action, Monash Institute of Pharmaceutical Sciences, 381 Royal Parade, Parkville, Victoria 3052, Australia
Dharshini Jeevarajah
- Avexa Ltd., 576 Swan Street Richmond, Victoria 3121, Australia
David I. Rhodes
- Avexa Ltd., 576 Swan Street Richmond, Victoria 3121, Australia
John Deadman
- Avexa Ltd., 576 Swan Street Richmond, Victoria 3121, Australia
David K. Chalmers
- Medicinal Chemistry and Drug Action, Monash Institute of Pharmaceutical Sciences, 381 Royal Parade, Parkville, Victoria 3052, Australia
Martin J. Scanlon
- Medicinal Chemistry and Drug Action, Monash Institute of Pharmaceutical Sciences, 381 Royal Parade, Parkville, Victoria 3052, Australia
- Corresponding author. Fax: +61 3 99039582.
Michael W. Parker
- Structural Biology Laboratory, St. Vincent’s Institute, 9 Princes Street, Fitzroy, Victoria 3065, Australia
- Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, 30 Flemington Road, Parkville, Victoria 3010, Australia
- Corresponding author at: Structural Biology Laboratory, St. Vincent’s Institute, 9 Princes Street, Fitzroy, Victoria 3065, Australia. Fax +61 3 94162676.

Received 8 January 2010; received in revised form 5 March 2010; accepted 9 March 2010. published online 12 March 2010.

Abstract

HIV integrase (IN) is an essential enzyme in HIV replication and an important target for drug design. IN has been shown to interact with a number of cellular and viral proteins during the integration process. Disruption of these important interactions could provide a mechanism for allosteric inhibition of IN. We present the highest resolution crystal structure of the IN core domain to date. We also present a crystal structure of the IN core domain in complex with sucrose which is bound at the dimer interface in a region that has previously been reported to bind integrase inhibitors.