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GM/CA @ APS

Users Highlights

Department of Energy Office of Science
GM/CA @ APS Sponsors:
National Institute of General Medical Sciences (NIGMS) and National Cancer Institute (NCI) of the National Institutes of Health (NIH)
 

Catechol O-methyltransferase

Ron Stenkamp and Bill Parson groups (University of Washington)

 

A neurobiology highlight comes from the groups of Ron Stenkamp and Bill Parson at the University of Washington, where crystal structures of human 108V and 108M catechol o-methyltransferase have been presented. Catechol O-methyltransferase (COMT) is involved in the metabolism of catecholamine neurotransmitters and plays a role in various neurological conditions including Parkinson's disease, obsessive-compulsive disorder, and some forms of schizophrenia. The human enzyme contains a polymorphism at residue 108. About 25% of U.S. and northern European caucasians are homozygous for Met108, while the rest of the population mainly has Val108. The Met108 variant has been linked to various neurological disorders, as well as to other conditions, including breast cancer. The crystal structures of both enzymes, in the presence of its co-substrate, S-adenosylmethionine (SAM), have been determined. The data set for 108M COMT was obtained at GM/CA's beamline 23-ID-D (1.3 Å resolution, R/Rfree = 0.124/0.167). Residue 108 is 16 Å away from the active site, and the polymorphism has little effect on the kinetic properties of the enzyme. 108M COMT is less stable than is 108V, but comparison of the structures does not indicate why that should be. The co-substrate SAM stabilizes 108M COMT, so the lack of significant structural differences might be ascribed to its presence. Efforts are underway to obtain crystals of unliganded COMT, to further investigate this puzzle.

Figure: A superposition of 108V COMT (cyan) and 108M COMT (magenta) showing the small structural differences near residue 108, the site of the major polymorphism in human COMT.

 

Citation:
Rutherford, K, Le Trong, I, Stenkamp, RE, Parson, WW. Crystal structures of human 108V and 108M catechol O-methyltransferase, J. Mol. Biol. 380 (1), 120-130 (2008). DOI: 10.1016/j.jmb.2008.04.040


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