2fy2
|
Structures of ligand bound human choline acetyltransferase provide insight into regulation of acetylcholine synthesis
OverviewOverview
Choline acetyltransferase (ChAT) catalyzes the synthesis of the, neurotransmitter acetylcholine from choline and acetyl-CoA, and its, presence is a defining feature of cholinergic neurons. We report the, structure of human ChAT to a resolution of 2.2 A along with structures for, binary complexes of ChAT with choline, CoA, and a nonhydrolyzable, acetyl-CoA analogue, S-(2-oxopropyl)-CoA. The ChAT-choline complex shows, which features of choline are important for binding and explains how, modifications of the choline trimethylammonium group can be tolerated by, the enzyme. A detailed model of the ternary Michaelis complex fully, supports the direct transfer of the acetyl group from acetyl-CoA to, choline through a mechanism similar to that seen in the serine hydrolases, for the formation of an acyl-enzyme intermediate. Domain movements, accompany CoA binding, and a surface loop, which is disordered in the, unliganded enzyme, becomes localized and binds directly to the phosphates, of CoA, stabilizing the complex. Interactions between this surface loop, and CoA may function to lower the KM for CoA and could be important for, phosphorylation-dependent regulation of ChAT activity.
DiseaseDisease
Known disease associated with this structure: Myasthenic syndrome, congenital, associated with episodic apnea OMIM:[118490]
About this StructureAbout this Structure
2FY2 is a Single protein structure of sequence from Homo sapiens. Active as Choline O-acetyltransferase, with EC number 2.3.1.6 Full crystallographic information is available from OCA.
ReferenceReference
Substrate binding and catalytic mechanism of human choline acetyltransferase., Kim AR, Rylett RJ, Shilton BH, Biochemistry. 2006 Dec 12;45(49):14621-31. PMID:17144655
Page seeded by OCA on Fri Feb 15 17:26:39 2008