2FY2

Structures of ligand bound human choline acetyltransferase provide insight into regulation of acetylcholine synthesis

Summary for 2FY2

• Entry DOI: 10.2210/pdb2fy2/pdb
• Related: 2fy3 2fy4 2fy5
• Descriptor: Choline O-acetyltransferase (2 entities in total)
• Functional Keywords: two domain, alpha-beta protein, transferase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 68113.35

Authors

Kim, A.R.,Rylett, R.J.,Shilton, B.H. (deposition date: 2006-02-07, release date: 2006-12-12, Last modification date: 2023-08-30)

Primary citation

Kim, A.R.,Rylett, R.J.,Shilton, B.H.
Substrate binding and catalytic mechanism of human choline acetyltransferase.
Biochemistry, 45:14621-14631, 2006

PubMed Abstract: 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.

PubMed: 17144655
DOI: 10.1021/bi061536l

Experimental method

X-RAY DIFFRACTION (2.25 Å)