View source for 5dot


==Crystal Structure of Human Carbamoyl phosphate synthetase I (CPS1), apo form==
<StructureSection load='5dot' size='340' side='right'caption='[[5dot]], [[Resolution|resolution]] 2.40&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[5dot]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5DOT OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5DOT FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=NI:NICKEL+(II)+ION'>NI</scene></td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CPS1 ([http://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'>[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>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=5dot FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5dot OCA], [http://pdbe.org/5dot PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5dot RCSB], [http://www.ebi.ac.uk/pdbsum/5dot PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5dot ProSAT]</span></td></tr>
</table>
== Disease ==
[[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>  
== Function ==
[[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. 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Human carbamoyl phosphate synthetase (CPS1), a 1500-residue multidomain enzyme, catalyzes the first step of ammonia detoxification to urea requiring N-acetyl-L-glutamate (NAG) as essential activator to prevent ammonia/amino acids depletion. Here we present the crystal structures of CPS1 in the absence and in the presence of NAG, clarifying the on/off-switching of the urea cycle by NAG. By binding at the C-terminal domain of CPS1, NAG triggers long-range conformational changes affecting the two distant phosphorylation domains. These changes, concerted with the binding of nucleotides, result in a dramatic remodeling that stabilizes the catalytically competent conformation and the building of the ~35 A-long tunnel that allows migration of the carbamate intermediate from its site of formation to the second phosphorylation site, where carbamoyl phosphate is produced. These structures allow rationalizing the effects of mutations found in patients with CPS1 deficiency (presenting hyperammonemia, mental retardation and even death), as exemplified here for some mutations.

Structure of human carbamoyl phosphate synthetase: deciphering the on/off switch of human ureagenesis.,de Cima S, Polo LM, Diez-Fernandez C, Martinez AI, Cervera J, Fita I, Rubio V Sci Rep. 2015 Nov 23;5:16950. doi: 10.1038/srep16950. PMID:26592762<ref>PMID:26592762</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 5dot" style="background-color:#fffaf0;"></div>

==See Also==
*[[Carbamoyl phosphate synthetase 3D structures|Carbamoyl phosphate synthetase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Human]]
[[Category: Large Structures]]
[[Category: Cima, S de]]
[[Category: Fita, I]]
[[Category: Polo, L M]]
[[Category: Rubio, V]]
[[Category: Adenosine triphosphate]]
[[Category: Allosteric site]]
[[Category: Ammonia]]
[[Category: Apo]]
[[Category: Carbamoyl phosphate]]
[[Category: Cps1 deficiency]]
[[Category: Hyperammonemia]]
[[Category: Ligase]]
[[Category: Multi-domain]]
[[Category: N-acetyl-l-glutamate]]
[[Category: Rare disease]]
[[Category: Urea cycle]]