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==In situ assembly of choline acetyltransferase ligands by a hydrothiolation reaction reveals key determinants for inhibitor design== | ==In situ assembly of choline acetyltransferase ligands by a hydrothiolation reaction reveals key determinants for inhibitor design== | ||
<StructureSection load='7amd' size='340' side='right'caption='[[7amd]]' scene=''> | <StructureSection load='7amd' size='340' side='right'caption='[[7amd]], [[Resolution|resolution]] 2.25Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7AMD OCA]. For a <b>guided tour on the structure components</b> use [ | <table><tr><td colspan='2'>[[7amd]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7AMD OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7AMD FirstGlance]. <br> | ||
</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=RMW:[[(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'>RMW</scene></td></tr> | ||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CHAT ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | |||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Choline_O-acetyltransferase Choline O-acetyltransferase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.3.1.6 2.3.1.6] </span></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7amd FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7amd OCA], [https://pdbe.org/7amd PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7amd RCSB], [https://www.ebi.ac.uk/pdbsum/7amd PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7amd ProSAT]</span></td></tr> | |||
</table> | </table> | ||
== Disease == | |||
[[https://www.uniprot.org/uniprot/CLAT_HUMAN CLAT_HUMAN]] Defects in CHAT are the cause of congenital myasthenic syndrome with episodic apnea (CMSEA) [MIM:[https://omim.org/entry/254210 254210]]; formerly known as familial infantile myasthenia gravis 2 (FIMG2). CMSEA is an autosomal recessive congenital myasthenic syndrome. Patients have myasthenic symptoms since birth or early infancy, negative tests for anti-AChR antibodies, and abrupt episodic crises with increased weakness, bulbar paralysis, and apnea precipitated by undue exertion, fever, or excitement.<ref>PMID:11172068</ref> <ref>PMID:12756141</ref> | |||
== Function == | |||
[[https://www.uniprot.org/uniprot/CLAT_HUMAN CLAT_HUMAN]] Catalyzes the reversible synthesis of acetylcholine (ACh) from acetyl CoA and choline at cholinergic synapses. | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
The potential drug target choline acetyltransferase (ChAT) catalyzes 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. | |||
In situ assembly of choline acetyltransferase ligands by a hydrothiolation reaction reveals key determinants for inhibitor design.,Wiktelius D, Allgardsson A, Bergstrom T, Hoster N, Akfur C, Forsgren N, Lejon C, Hedenstrom M, Linusson A, Ekstrom F Angew Chem Int Ed Engl. 2020 Oct 20. doi: 10.1002/anie.202011989. PMID:33079431<ref>PMID:33079431</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 7amd" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Choline O-acetyltransferase]] | |||
[[Category: Human]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Akfur C]] | [[Category: Akfur, C]] | ||
[[Category: Allgardsson A]] | [[Category: Allgardsson, A]] | ||
[[Category: Bergstrom T]] | [[Category: Bergstrom, T]] | ||
[[Category: Ekstrom | [[Category: Ekstrom, F J]] | ||
[[Category: Forsgren N]] | [[Category: Forsgren, N]] | ||
[[Category: Hedenstrom M]] | [[Category: Hedenstrom, M]] | ||
[[Category: Hoster N]] | [[Category: Hoster, N]] | ||
[[Category: Lejon C]] | [[Category: Lejon, C]] | ||
[[Category: Linusson A]] | [[Category: Linusson, A]] | ||
[[Category: Wiktelius D]] | [[Category: Wiktelius, D]] | ||
[[Category: Avp]] | |||
[[Category: Chat]] | |||
[[Category: Hydrothiolation]] | |||
[[Category: Inhibitor]] | |||
[[Category: Transferase]] | |||