7AMD
In situ assembly of choline acetyltransferase ligands by a hydrothiolation reaction reveals key determinants for inhibitor design
Summary for 7AMD
| Entry DOI | 10.2210/pdb7amd/pdb |
| Descriptor | Choline O-acetyltransferase, [[(2~{R},3~{S},4~{R},5~{R})-5-(6-aminopurin-9-yl)-4-oxidanyl-3-phosphonooxy-oxolan-2-yl]methoxy-oxidanyl-phosphoryl] [(3~{R})-2,2-dimethyl-4-[[3-[2-[(1~{R})-2-(1-methylpyridin-4-yl)-1-naphthalen-1-yl-ethyl]sulfanylethylamino]-3-oxidanylidene-propyl]amino]-3-oxidanyl-4-oxidanylidene-butyl] hydrogen phosphate, SODIUM ION, ... (4 entities in total) |
| Functional Keywords | chat, inhibitor, avp, hydrothiolation, transferase |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 1 |
| Total formula weight | 69173.19 |
| Authors | Allgardsson, A.,Ekstrom, F.J.,Wiktelius, D.,Bergstrom, T.,Hoster, N.,Akfur, C.,Forsgren, N.,Lejon, C.,Hedenstrom, M.,Linusson, A. (deposition date: 2020-10-08, release date: 2020-10-28, Last modification date: 2024-01-31) |
| Primary citation | Wiktelius, D.,Allgardsson, A.,Bergstrom, T.,Hoster, N.,Akfur, C.,Forsgren, N.,Lejon, C.,Hedenstrom, M.,Linusson, A.,Ekstrom, F. In Situ Assembly of Choline Acetyltransferase Ligands by a Hydrothiolation Reaction Reveals Key Determinants for Inhibitor Design. Angew.Chem.Int.Ed.Engl., 60:813-819, 2021 Cited by PubMed Abstract: The potential drug target choline acetyltransferase (ChAT) catalyses the production of the neurotransmitter acetylcholine in cholinergic neurons, T-cells, and B-cells. Herein, we show that arylvinylpyridiniums (AVPs), the most widely studied class of ChAT inhibitors, act as substrate in an unusual coenzyme A-dependent hydrothiolation reaction. This in situ synthesis yields an adduct that is the actual enzyme inhibitor. The adduct is deeply buried in the active site tunnel of ChAT and interactions with a hydrophobic pocket near the choline binding site have major implications for the molecular recognition of inhibitors. Our findings clarify the inhibition mechanism of AVPs, establish a drug modality that exploits a target-catalysed reaction between exogenous and endogenous precursors, and provide new directions for the development of ChAT inhibitors with improved potency and bioactivity. PubMed: 33079431DOI: 10.1002/anie.202011989 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.25 Å) |
Structure validation
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