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7amd

From Proteopedia

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In situ assembly of choline acetyltransferase ligands by a hydrothiolation reaction reveals key determinants for inhibitor design

Structural highlights

7amd is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.25Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

CLAT_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]

Function

CLAT_HUMAN Catalyzes the reversible synthesis of acetylcholine (ACh) from acetyl CoA and choline at cholinergic synapses.

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^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Ohno K, Tsujino A, Brengman JM, Harper CM, Bajzer Z, Udd B, Beyring R, Robb S, Kirkham FJ, Engel AG. Choline acetyltransferase mutations cause myasthenic syndrome associated with episodic apnea in humans. Proc Natl Acad Sci U S A. 2001 Feb 13;98(4):2017-22. PMID:11172068 doi:10.1073/pnas.98.4.2017
↑ Kraner S, Laufenberg I, Strassburg HM, Sieb JP, Steinlein OK. Congenital myasthenic syndrome with episodic apnea in patients homozygous for a CHAT missense mutation. Arch Neurol. 2003 May;60(5):761-3. PMID:12756141 doi:10.1001/archneur.60.5.761
↑ 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. 2020 Oct 20. doi: 10.1002/anie.202011989. PMID:33079431 doi:http://dx.doi.org/10.1002/anie.202011989

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 See Also
6 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/7amd"

@@ Line 3: / Line 3: @@
 <StructureSection load='7amd' size='340' side='right'caption='[[7amd]], [[Resolution|resolution]] 2.25&Aring;' scene=''>
 == Structural highlights ==
-<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>
+<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>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.25&#8491;</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='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='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>
 == 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>
+[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.
+[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 ==
@@ Line 22: / Line 21: @@
 </div>
 <div class="pdbe-citations 7amd" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Choline O-acetyltransferase|Choline O-acetyltransferase]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
-[[Category: Choline O-acetyltransferase]]
+[[Category: Homo sapiens]]
-[[Category: Human]]
 [[Category: Large Structures]]
-[[Category: Akfur, C]]
+[[Category: Akfur C]]
-[[Category: Allgardsson, A]]
+[[Category: Allgardsson A]]
-[[Category: Bergstrom, T]]
+[[Category: Bergstrom T]]
-[[Category: Ekstrom, F J]]
+[[Category: Ekstrom FJ]]
-[[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]]

7amd

From Proteopedia

Current revision

In situ assembly of choline acetyltransferase ligands by a hydrothiolation reaction reveals key determinants for inhibitor design

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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