View source for 6w2j


==CPS1 bound to allosteric inhibitor H3B-374==
<StructureSection load='6w2j' size='340' side='right'caption='[[6w2j]], [[Resolution|resolution]] 2.62&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6w2j]] is a 2 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=6W2J OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6W2J FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.62&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=374:(2-fluoranyl-4-methoxy-phenyl)-[(3~{R},5~{R})-4-(2-fluoranyl-4-methoxy-phenyl)carbonyl-3,5-dimethyl-piperazin-1-yl]methanone'>374</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</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=6w2j FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6w2j OCA], [https://pdbe.org/6w2j PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6w2j RCSB], [https://www.ebi.ac.uk/pdbsum/6w2j PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6w2j ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/CPSM_HUMAN CPSM_HUMAN] Defects in CPS1 are the cause of carbamoyl phosphate synthetase 1 deficiency (CPS1D) [MIM:[https://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> 
== Function ==
[https://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.
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Carbamoyl phosphate synthetase 1 (CPS1) is a potential synthetic lethal target in LKB1-deficient nonsmall cell lung cancer, where its overexpression supports the production of pyrimidine synthesis. In other cancer types, CPS1 overexpression and activity may prevent the accumulation of toxic levels of intratumoral ammonia to support tumor growth. Herein we report the discovery of a novel series of potent and selective small-molecule inhibitors of CPS1. Piperazine 2 was initially identified as a promising CPS1 inhibitor through a high-throughput screening effort. Subsequent structure-activity relationship optimization and structure-based drug design led to the discovery of piperazine H3B-616 (25), a potent allosteric inhibitor of CPS1 (IC50 = 66 nM).

Discovery of 2,6-Dimethylpiperazines as Allosteric Inhibitors of CPS1.,Rolfe A, Yao S, Nguyen TV, Omoto K, Colombo F, Virrankoski M, Vaillancourt FH, Yu L, Cook A, Reynolds D, Ioannidis S, Zhu P, Larsen NA, Bolduc DM ACS Med Chem Lett. 2020 May 26;11(6):1305-1309. doi:, 10.1021/acsmedchemlett.0c00145. eCollection 2020 Jun 11. PMID:32551016<ref>PMID:32551016</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6w2j" style="background-color:#fffaf0;"></div>

==See Also==
*[[Carbamoyl phosphate synthetase 3D structures|Carbamoyl phosphate synthetase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Larsen NA]]
[[Category: Nguyen TV]]