7amd: Difference between revisions
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<StructureSection load='7amd' size='340' side='right'caption='[[7amd]], [[Resolution|resolution]] 2.25Å' scene=''> | <StructureSection load='7amd' size='340' side='right'caption='[[7amd]], [[Resolution|resolution]] 2.25Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[7amd]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/ | <table><tr><td colspan='2'>[[7amd]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. 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='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='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.25Å</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='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> | <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 == | == 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 == | == 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;"> | <div style="background-color:#fffaf0;"> | ||
== Publication Abstract from PubMed == | == Publication Abstract from PubMed == | ||
| Line 22: | Line 21: | ||
</div> | </div> | ||
<div class="pdbe-citations 7amd" style="background-color:#fffaf0;"></div> | <div class="pdbe-citations 7amd" style="background-color:#fffaf0;"></div> | ||
==See Also== | |||
*[[Choline O-acetyltransferase|Choline O-acetyltransferase]] | |||
== References == | == References == | ||
<references/> | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: | [[Category: Homo sapiens]] | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Akfur | [[Category: Akfur C]] | ||
[[Category: Allgardsson | [[Category: Allgardsson A]] | ||
[[Category: Bergstrom | [[Category: Bergstrom T]] | ||
[[Category: Ekstrom | [[Category: Ekstrom FJ]] | ||
[[Category: Forsgren | [[Category: Forsgren N]] | ||
[[Category: Hedenstrom | [[Category: Hedenstrom M]] | ||
[[Category: Hoster | [[Category: Hoster N]] | ||
[[Category: Lejon | [[Category: Lejon C]] | ||
[[Category: Linusson | [[Category: Linusson A]] | ||
[[Category: Wiktelius | [[Category: Wiktelius D]] | ||
Latest revision as of 15:12, 1 February 2024
In situ assembly of choline acetyltransferase ligands by a hydrothiolation reaction reveals key determinants for inhibitor designIn situ assembly of choline acetyltransferase ligands by a hydrothiolation reaction reveals key determinants for inhibitor design
Structural highlights
DiseaseCLAT_HUMAN Defects in CHAT are the cause of congenital myasthenic syndrome with episodic apnea (CMSEA) [MIM: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.[1] [2] FunctionCLAT_HUMAN Catalyzes the reversible synthesis of acetylcholine (ACh) from acetyl CoA and choline at cholinergic synapses. Publication Abstract from PubMedThe 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[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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