6uel

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'''Unreleased structure'''
 
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The entry 6uel is ON HOLD until Paper Publication
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==CPS1 bound to allosteric inhibitor H3B-193==
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<StructureSection load='6uel' size='340' side='right'caption='[[6uel]], [[Resolution|resolution]] 1.90&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[6uel]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6UEL OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6UEL FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=Q5A:N~1~-[(4-fluorophenyl)methyl]-N~1~-methyl-N~4~-(4-methyl-1,3-thiazol-2-yl)piperidine-1,4-dicarboxamide'>Q5A</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
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<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Carbamoyl-phosphate_synthase_(ammonia) Carbamoyl-phosphate synthase (ammonia)], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=6.3.4.16 6.3.4.16] </span></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6uel FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6uel OCA], [http://pdbe.org/6uel PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6uel RCSB], [http://www.ebi.ac.uk/pdbsum/6uel PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6uel ProSAT]</span></td></tr>
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</table>
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== Disease ==
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[[http://www.uniprot.org/uniprot/CPSM_HUMAN CPSM_HUMAN]] Defects in CPS1 are the cause of carbamoyl phosphate synthetase 1 deficiency (CPS1D) [MIM:[http://omim.org/entry/237300 237300]]. CPS1D is an autosomal recessive disorder of the urea cycle causing hyperammonemia. Clinical features include protein intolerance, intermittent ataxia, seizures, lethargy, developmental delay and mental retardation.<ref>PMID:9711878</ref> <ref>PMID:12955727</ref> <ref>PMID:12655559</ref> <ref>PMID:11388595</ref> <ref>PMID:11474210</ref> <ref>PMID:15617192</ref> <ref>PMID:15164414</ref> <ref>PMID:16737834</ref> <ref>PMID:17310273</ref> <ref>PMID:20578160</ref> <ref>PMID:20520828</ref> <ref>PMID:21120950</ref> Note=Genetic variations in CPS1 influence the availability of precursors for nitric oxide (NO) synthesis and play a role in clinical situations where endogenous NO production is critically important, such as neonatal pulmonary hypertension, increased pulmonary artery pressure following surgical repair of congenital heart defects or hepatovenocclusive disease following bone marrow transplantation. Infants with neonatal pulmonary hypertension homozygous for Thr-1406 have lower L-arginine concentrations than neonates homozygous for Asn-1406.<ref>PMID:20520828</ref>
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== Function ==
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[[http://www.uniprot.org/uniprot/CPSM_HUMAN CPSM_HUMAN]] Involved in the urea cycle of ureotelic animals where the enzyme plays an important role in removing excess ammonia from the cell.
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Carbamoyl phosphate synthetase 1 (CPS1) catalyzes the first step in the ammonia-detoxifying urea cycle, converting ammonia to carbamoyl phosphate under physiologic conditions. In cancer, CPS1 overexpression supports pyrimidine synthesis to promote tumor growth in some cancer types, while in others CPS1 activity prevents the buildup of toxic levels of intratumoral ammonia to allow for sustained tumor growth. Targeted CPS1 inhibitors may, therefore, provide a therapeutic benefit for cancer patients with tumors overexpressing CPS1. Herein, we describe the discovery of small-molecule CPS1 inhibitors that bind to a previously unknown allosteric pocket to block ATP hydrolysis in the first step of carbamoyl phosphate synthesis. CPS1 inhibitors are active in cellular assays, blocking both urea synthesis and CPS1 support of the pyrimidine biosynthetic pathway, while having no activity against CPS2. These newly discovered CPS1 inhibitors are a first step toward providing researchers with valuable tools for probing CPS1 cancer biology.
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Authors: Larsen, N.A., Nguyen, T.V.
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Small Molecule Inhibition of CPS1 Activity through an Allosteric Pocket.,Yao S, Nguyen TV, Rolfe A, Agrawal AA, Ke J, Peng S, Colombo F, Yu S, Bouchard P, Wu J, Huang KC, Bao X, Omoto K, Selvaraj A, Yu L, Ioannidis S, Vaillancourt FH, Zhu P, Larsen NA, Bolduc DM Cell Chem Biol. 2020 Jan 28. pii: S2451-9456(20)30034-9. doi:, 10.1016/j.chembiol.2020.01.009. PMID:32017919<ref>PMID:32017919</ref>
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Description: CPS1 bound to allosteric inhibitor H3B-193
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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[[Category: Unreleased Structures]]
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</div>
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[[Category: Larsen, N.A]]
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<div class="pdbe-citations 6uel" style="background-color:#fffaf0;"></div>
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[[Category: Nguyen, T.V]]
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== References ==
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<references/>
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__TOC__
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</StructureSection>
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[[Category: Large Structures]]
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[[Category: Larsen, N A]]
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[[Category: Nguyen, T V]]
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[[Category: Allosteric inhibitor]]
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[[Category: Cps1]]
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[[Category: Ligase]]
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[[Category: Ligase-ligase inhibitor complex]]
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[[Category: Transferase]]

Revision as of 09:56, 18 March 2020

CPS1 bound to allosteric inhibitor H3B-193

PDB ID 6uel

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