6xp1

From Proteopedia

(Difference between revisions)

Revision as of 08:12, 11 November 2020

Structure of human PYCR1 complexed with L-thiazolidine-2-carboxylate

Structural highlights

6xp1 is a 5 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	,
Gene:	PYCR1 (HUMAN)
Activity:	Pyrroline-5-carboxylate reductase, with EC number 1.5.1.2
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

[P5CR1_HUMAN] Defects in PYCR1 are the cause of cutis laxa autosomal recessive type 2B (ARCL2B) [MIM: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.^[1] ^[2] Defects in PYCR1 are the cause of cutis laxa, autosomal recessive, type 3B (ARCL3B) [MIM:614438]. ARCL3B is a disorder characterized by an aged appearance with distinctive facial features, sparse hair, ophthalmologic abnormalities, intrauterine growth retardation, and cutis laxa.^[3] ^[4]

Function

[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.^[5] ^[6]

Publication Abstract from PubMed

Pyrroline-5-carboxylate reductase 1 (PYCR1) catalyzes the biosynthetic half-reaction of the proline cycle by reducing Delta(1)-pyrroline-5-carboxylate (P5C) to proline through the oxidation of NAD(P)H. Many cancers alter their proline metabolism by upregulating the proline cycle and proline biosynthesis, and knockdowns of PYCR1 lead to decreased cell proliferation. Thus, evidence is growing for PYCR1 as a potential cancer therapy target. Inhibitors of cancer targets are useful as chemical probes for studying cancer mechanisms and starting compounds for drug discovery; however, there is a notable lack of validated inhibitors for PYCR1. To fill this gap, we performed a small-scale focused screen of proline analogs using X-ray crystallography. Five inhibitors of human PYCR1 were discovered: L-tetrahydro-2-furoic acid, cyclopentanecarboxylate, L-thiazolidine-4-carboxylate, L-thiazolidine-2-carboxylate, and N-formyl L-proline (NFLP). The most potent inhibitor was NFLP, which had a competitive (with P5C) inhibition constant of 100 mM. The structure of PYCR1 complexed with NFLP shows that inhibitor binding is accompanied by conformational changes in the active site, including the translation of an a-helix by 1 A. These changes are unique to NFLP and enable additional hydrogen bonds with the enzyme. NFLP was also shown to phenocopy the PYCR1knockdown in MCF10A H-RASV12 breast cancer cells by inhibiting de novo proline biosynthesis and impairing spheroidal growth. In summary, we generated the first validated chemical probe of PYCR1 and demonstrated proof-of-concept for screening proline analogs to discover inhibitors of the proline cycle.

In Crystallo Screening for Proline Analog Inhibitors of the Proline Cycle Enzyme PYCR1.,Christensen EM, Bogner AN, Vandekeere A, Tam GS, Patel SM, Becker DF, Fendt SM, Tanner JJ J Biol Chem. 2020 Oct 27. pii: RA120.016106. doi: 10.1074/jbc.RA120.016106. PMID:33109600^[7]

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

References

↑ Reversade B, Escande-Beillard N, Dimopoulou A, Fischer B, Chng SC, Li Y, Shboul M, Tham PY, Kayserili H, Al-Gazali L, Shahwan M, Brancati F, Lee H, O'Connor BD, Schmidt-von Kegler M, Merriman B, Nelson SF, Masri A, Alkazaleh F, Guerra D, Ferrari P, Nanda A, Rajab A, Markie D, Gray M, Nelson J, Grix A, Sommer A, Savarirayan R, Janecke AR, Steichen E, Sillence D, Hausser I, Budde B, Nurnberg G, Nurnberg P, Seemann P, Kunkel D, Zambruno G, Dallapiccola B, Schuelke M, Robertson S, Hamamy H, Wollnik B, Van Maldergem L, Mundlos S, Kornak U. Mutations in PYCR1 cause cutis laxa with progeroid features. Nat Genet. 2009 Sep;41(9):1016-21. doi: 10.1038/ng.413. Epub 2009 Aug 2. PMID:19648921 doi:10.1038/ng.413
↑ Guernsey DL, Jiang H, Evans SC, Ferguson M, Matsuoka M, Nightingale M, Rideout AL, Provost S, Bedard K, Orr A, Dube MP, Ludman M, Samuels ME. Mutation in pyrroline-5-carboxylate reductase 1 gene in families with cutis laxa type 2. Am J Hum Genet. 2009 Jul;85(1):120-9. doi: 10.1016/j.ajhg.2009.06.008. Epub 2009 , Jul 2. PMID:19576563 doi:10.1016/j.ajhg.2009.06.008
↑ Reversade B, Escande-Beillard N, Dimopoulou A, Fischer B, Chng SC, Li Y, Shboul M, Tham PY, Kayserili H, Al-Gazali L, Shahwan M, Brancati F, Lee H, O'Connor BD, Schmidt-von Kegler M, Merriman B, Nelson SF, Masri A, Alkazaleh F, Guerra D, Ferrari P, Nanda A, Rajab A, Markie D, Gray M, Nelson J, Grix A, Sommer A, Savarirayan R, Janecke AR, Steichen E, Sillence D, Hausser I, Budde B, Nurnberg G, Nurnberg P, Seemann P, Kunkel D, Zambruno G, Dallapiccola B, Schuelke M, Robertson S, Hamamy H, Wollnik B, Van Maldergem L, Mundlos S, Kornak U. Mutations in PYCR1 cause cutis laxa with progeroid features. Nat Genet. 2009 Sep;41(9):1016-21. doi: 10.1038/ng.413. Epub 2009 Aug 2. PMID:19648921 doi:10.1038/ng.413
↑ Lin DS, Chang JH, Liu HL, Wei CH, Yeung CY, Ho CS, Shu CH, Chiang MF, Chuang CK, Huang YW, Wu TY, Jian YR, Huang ZD, Lin SP. Compound heterozygous mutations in PYCR1 further expand the phenotypic spectrum of De Barsy syndrome. Am J Med Genet A. 2011 Dec;155A(12):3095-9. doi: 10.1002/ajmg.a.34326. Epub 2011 , Nov 3. PMID:22052856 doi:10.1002/ajmg.a.34326
↑ Reversade B, Escande-Beillard N, Dimopoulou A, Fischer B, Chng SC, Li Y, Shboul M, Tham PY, Kayserili H, Al-Gazali L, Shahwan M, Brancati F, Lee H, O'Connor BD, Schmidt-von Kegler M, Merriman B, Nelson SF, Masri A, Alkazaleh F, Guerra D, Ferrari P, Nanda A, Rajab A, Markie D, Gray M, Nelson J, Grix A, Sommer A, Savarirayan R, Janecke AR, Steichen E, Sillence D, Hausser I, Budde B, Nurnberg G, Nurnberg P, Seemann P, Kunkel D, Zambruno G, Dallapiccola B, Schuelke M, Robertson S, Hamamy H, Wollnik B, Van Maldergem L, Mundlos S, Kornak U. Mutations in PYCR1 cause cutis laxa with progeroid features. Nat Genet. 2009 Sep;41(9):1016-21. doi: 10.1038/ng.413. Epub 2009 Aug 2. PMID:19648921 doi:10.1038/ng.413
↑ Meng Z, Lou Z, Liu Z, Li M, Zhao X, Bartlam M, Rao Z. Crystal structure of human pyrroline-5-carboxylate reductase. J Mol Biol. 2006 Jun 23;359(5):1364-77. Epub 2006 May 11. PMID:16730026 doi:10.1016/j.jmb.2006.04.053
↑ Christensen EM, Bogner AN, Vandekeere A, Tam GS, Patel SM, Becker DF, Fendt SM, Tanner JJ. In Crystallo Screening for Proline Analog Inhibitors of the Proline Cycle Enzyme PYCR1. J Biol Chem. 2020 Oct 27. pii: RA120.016106. doi: 10.1074/jbc.RA120.016106. PMID:33109600 doi:http://dx.doi.org/10.1074/jbc.RA120.016106

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/6xp1"

@@ Line 1: / Line 1: @@
 ==Structure of human PYCR1 complexed with L-thiazolidine-2-carboxylate==
-<StructureSection load='6xp1' size='340' side='right'caption='[[6xp1]]' scene=''>
+<StructureSection load='6xp1' size='340' side='right'caption='[[6xp1]], [[Resolution|resolution]] 1.75&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6XP1 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6XP1 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6xp1]] is a 5 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=6XP1 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6XP1 FirstGlance]. <br>
-</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=6xp1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6xp1 OCA], [http://pdbe.org/6xp1 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6xp1 RCSB], [http://www.ebi.ac.uk/pdbsum/6xp1 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6xp1 ProSAT]</span></td></tr>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=T2C:(2S)-1,3-thiazolidine-2-carboxylic+acid'>T2C</scene></td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">PYCR1 ([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/Pyrroline-5-carboxylate_reductase Pyrroline-5-carboxylate reductase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.5.1.2 1.5.1.2] </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=6xp1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6xp1 OCA], [http://pdbe.org/6xp1 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6xp1 RCSB], [http://www.ebi.ac.uk/pdbsum/6xp1 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6xp1 ProSAT]</span></td></tr>
 </table>
+== Disease ==
+[[http://www.uniprot.org/uniprot/P5CR1_HUMAN P5CR1_HUMAN]] Defects in PYCR1 are the cause of cutis laxa autosomal recessive type 2B (ARCL2B) [MIM:[http://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:[http://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 ==
+[[http://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 1 (PYCR1) catalyzes the biosynthetic half-reaction of the proline cycle by reducing Delta(1)-pyrroline-5-carboxylate (P5C) to proline through the oxidation of NAD(P)H. Many cancers alter their proline metabolism by upregulating the proline cycle and proline biosynthesis, and knockdowns of PYCR1 lead to decreased cell proliferation. Thus, evidence is growing for PYCR1 as a potential cancer therapy target. Inhibitors of cancer targets are useful as chemical probes for studying cancer mechanisms and starting compounds for drug discovery; however, there is a notable lack of validated inhibitors for PYCR1. To fill this gap, we performed a small-scale focused screen of proline analogs using X-ray crystallography. Five inhibitors of human PYCR1 were discovered: L-tetrahydro-2-furoic acid, cyclopentanecarboxylate, L-thiazolidine-4-carboxylate, L-thiazolidine-2-carboxylate, and N-formyl L-proline (NFLP). The most potent inhibitor was NFLP, which had a competitive (with P5C) inhibition constant of 100 mM. The structure of PYCR1 complexed with NFLP shows that inhibitor binding is accompanied by conformational changes in the active site, including the translation of an a-helix by 1 A. These changes are unique to NFLP and enable additional hydrogen bonds with the enzyme. NFLP was also shown to phenocopy the PYCR1knockdown in MCF10A H-RASV12 breast cancer cells by inhibiting de novo proline biosynthesis and impairing spheroidal growth. In summary, we generated the first validated chemical probe of PYCR1 and demonstrated proof-of-concept for screening proline analogs to discover inhibitors of the proline cycle.
+In Crystallo Screening for Proline Analog Inhibitors of the Proline Cycle Enzyme PYCR1.,Christensen EM, Bogner AN, Vandekeere A, Tam GS, Patel SM, Becker DF, Fendt SM, Tanner JJ J Biol Chem. 2020 Oct 27. pii: RA120.016106. doi: 10.1074/jbc.RA120.016106. PMID:33109600<ref>PMID:33109600</ref>
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+</div>
+<div class="pdbe-citations 6xp1" style="background-color:#fffaf0;"></div>
+== References ==
+<references/>
 __TOC__
 </StructureSection>
+[[Category: Human]]
 [[Category: Large Structures]]
-[[Category: Christensen EM]]
+[[Category: Pyrroline-5-carboxylate reductase]]
-[[Category: Tanner JJ]]
+[[Category: Christensen, E M]]
+[[Category: Tanner, J J]]
+[[Category: Amino-acid biosynthesis]]
+[[Category: Oxidoreductase]]
+[[Category: Proline biosynthesis]]

6xp1

From Proteopedia

Revision as of 08:12, 11 November 2020

Structure of human PYCR1 complexed with L-thiazolidine-2-carboxylate

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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