View source for 5uax


==Structure of apo human PYCR-1 crystallized in space group C2==
<StructureSection load='5uax' size='340' side='right'caption='[[5uax]], [[Resolution|resolution]] 1.85&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[5uax]] is a 5 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=5UAX OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5UAX 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]] 1.85&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</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=5uax FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5uax OCA], [https://pdbe.org/5uax PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5uax RCSB], [https://www.ebi.ac.uk/pdbsum/5uax PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5uax ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/P5CR1_HUMAN P5CR1_HUMAN] Defects in PYCR1 are the cause of cutis laxa autosomal recessive type 2B (ARCL2B) [MIM:[https://omim.org/entry/612940 612940]. A multisystem disorder characterized by the appearance of premature aging, wrinkled and lax skin with reduced elasticity, joint laxity, craniofacial dysmorphic features, intrauterine growth retardation with some degree of postnatal growth deficiency, and developmental delay.<ref>PMID:19648921</ref> <ref>PMID:19576563</ref>   Defects in PYCR1 are the cause of cutis laxa, autosomal recessive, type 3B (ARCL3B) [MIM:[https://omim.org/entry/614438 614438]. ARCL3B is a disorder characterized by an aged appearance with distinctive facial features, sparse hair, ophthalmologic abnormalities, intrauterine growth retardation, and cutis laxa.<ref>PMID:19648921</ref> <ref>PMID:22052856</ref> 
== Function ==
[https://www.uniprot.org/uniprot/P5CR1_HUMAN P5CR1_HUMAN] Housekeeping enzyme that catalyzes the last step in proline biosynthesis. Can utilize both NAD and NADP, but has higher affinity for NAD. Involved in the cellular response to oxidative stress.<ref>PMID:19648921</ref> <ref>PMID:16730026</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Pyrroline-5-carboxylate reductase (PYCR) is the final enzyme in proline biosynthesis, catalyzing the NAD(P)H-dependent reduction of Delta1-pyrroline-5-carboxylate (P5C) to proline. Mutations in the PYCR1 gene alter mitochondrial function and cause the connective tissue disorder cutis laxa. Furthermore, PYCR1 is overexpressed in multiple cancers, and the PYCR1 knockout suppresses tumorigenic growth, suggesting PYCR1 is a potential cancer target. However, inhibitor development has been stymied by limited mechanistic details for the enzyme, particularly in light of a previous crystallographic study that placed the cofactor binding site in the C-terminal domain rather than the anticipated Rossmann fold of the N-terminal domain. To fill this gap, we report crystallographic, sedimentation velocity, and kinetics data for human PYCR1. Structures of binary complexes of PYCR1 with NADPH or proline determined at 1.9 A resolution provide insight into cofactor and substrate recognition. We see NADPH bound to the Rossmann fold, over 25 A from the previously proposed site. The 1.85 A resolution structure of a ternary complex containing NADPH and a P5C/proline analog provides a model of the Michaelis complex formed during hydride transfer. Sedimentation velocity shows that PYCR1 forms a concentration-dependent decamer in solution, consistent with the pentamer-of-dimers assembly seen crystallographically. Kinetic and mutational analysis confirmed several features seen in the crystal structure, including the importance of a hydrogen bond between Thr248 and the substrate as well as limited cofactor discrimination.

Resolving the Cofactor Binding Site in the Proline Biosynthetic Enzyme Human Pyrroline-5-Carboxylate Reductase 1.,Christensen EM, Patel SM, Korasick DA, Campbell AC, Krause KL, Becker DF, Tanner JJ J Biol Chem. 2017 Mar 3. pii: jbc.M117.780288. doi: 10.1074/jbc.M117.780288. PMID:28258219<ref>PMID:28258219</ref>

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

==See Also==
*[[Pyrroline-5-carboxylate reductase|Pyrroline-5-carboxylate reductase]]
== References ==
<references/>
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Tanner JJ]]