Crystal structures of human 108V and 108M catechol O-methyltransferase

Area of Science:

• Biochemistry
• Structural Biology
• Pharmacology

Background:

• Catechol O-methyltransferase (COMT) is vital for metabolizing neurotransmitters and estrogens.
• COMT inhibitors are explored for Parkinson's disease treatment, but human and rat enzyme differences pose challenges.
• A common human COMT polymorphism (Val108Met) affects enzyme stability and activity.

Purpose of the Study:

• To elucidate the structural basis of the Val108Met polymorphism in human COMT.
• To compare the crystal structures of human COMT 108V and 108M variants bound to SAM and a substrate analog.
• To understand how the polymorphism influences enzyme stability and substrate specificity.

Main Methods:

• X-ray crystallography was used to determine the structures of human COMT 108V and 108M variants.
• The variants were crystallized in complex with S-adenosylmethionine (SAM) and 3,5-dinitrocatechol.
• Structural comparisons were performed using C(alpha) RMSD analysis and detailed examination of residue interactions.

Main Results:

• The 108V and 108M COMT structures are highly similar (C(alpha) RMSD=0.2 A), with superposable active sites.
• The methionine side chain in 108M packs tighter, causing a 0.7-A backbone displacement near residue 108, affecting the SAM-binding site.
• Differences in conserved residues exist in the SAM and catechol-binding sites between human and rat COMT, and human COMT has additional cysteines potentially involved in aggregation.

Conclusions:

• The Val108Met polymorphism subtly alters human COMT structure, influencing SAM binding and potentially enzyme function.
• Structural differences between human and rat COMT explain variations in substrate specificity.
• Understanding these structural nuances is critical for designing effective COMT-targeted therapeutics for neurological disorders.