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.
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