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J. Biol. Chem., Vol. 277, Issue 37, 34336-34342, September 13, 2002

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Structures of the Complexes of a Potent Anti-HIV Protein Cyanovirin-N and High Mannose Oligosaccharides^*

Istvan Botos, Barry R. O'Keefe^§, Shilpa R. Shenoy^§, Laura K. Cartner^¶, Daniel M. Ratner^**, Peter H. Seeberger, Michael R. Boyd^§§, and Alexander Wlodawer^¶¶

From the  Macromolecular Crystallography Laboratory, NCI, National Institutes of Health, Frederick, Maryland 21702-1201, ^§ Molecular Targets Drug Discovery Program, Center for Cancer Research, NCI-Frederick, National Institutes of Health, Frederick, Maryland 21702, ^¶ Intramural Research Support Program, SAIC-Frederick, Frederick, Maryland 21702,  Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, and the ^§§ USA Cancer Research Institute, College of Medicine, University of South Alabama, Mobile, Alabama 36688

The development of anti-human immunodeficiency virus (HIV) microbicides for either topical or ex vivo use is of considerable interest, mainly due to the difficulties in creating a vaccine that would be active against multiple clades of HIV. Cyanovirin-N (CV-N), an 11-kDa protein from the cyanobacterium (blue-green algae) Nostoc ellipsosporum with potent virucidal activity, was identified in the search for such antiviral agents. The binding of CV-N to the heavily glycosylated HIV envelope protein gp120 is carbohydrate-dependent. Since previous CV-N-dimannose structures could not fully explain CV-N-oligomannose binding, we determined the crystal structures of recombinant CV-N complexed to Man-9 and a synthetic hexamannoside, at 2.5- and 2.4-Å resolution, respectively. CV-N is a three-dimensional domain-swapped dimer in the crystal structures with two primary sites near the hinge region and two secondary sites on the opposite ends of the dimer. The binding interface is constituted of three stacked 12-linked mannose rings for Man-9 and two stacked mannose rings for hexamannoside with the rest of the saccharide molecules pointing to the solution. These structures show unequivocally the binding geometry of high mannose sugars to CV-N, permitting a better understanding of carbohydrate binding to this potential new lead for the design of drugs against AIDS.

The atomic coordinates and the structure factors (code 1M5J, 1M5M) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

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