View source for 9q45


==Quaternary complex of PYCR1 with the allosteric inhibitor 1-benzyl-1H-1,3-benzodiazole-2-sulfonic acid in a remote site and NADH and (S)-tetrahydrofuran-2-carboxylic acid in the active site==
<StructureSection load='9q45' size='340' side='right'caption='[[9q45]], [[Resolution|resolution]] 1.79&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[9q45]] 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=9Q45 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9Q45 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]] 1.79&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1CFK:1-benzyl-1H-1,3-benzimidazole-2-sulfonic+acid'>A1CFK</scene>, <scene name='pdbligand=NAI:1,4-DIHYDRONICOTINAMIDE+ADENINE+DINUCLEOTIDE'>NAI</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene>, <scene name='pdbligand=TFB:TETRAHYDROFURAN-2-CARBOXYLIC+ACID'>TFB</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=9q45 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9q45 OCA], [https://pdbe.org/9q45 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9q45 RCSB], [https://www.ebi.ac.uk/pdbsum/9q45 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9q45 ProSAT]</span></td></tr>
</table>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Delta1-pyrroline-5-carboxylate (P5C) reductase 1 (PYCR1) catalyzes the NAD(P)H-dependent conversion of L-P5C to L-proline and is one of the most consistently upregulated metabolic enzymes in cancer cells. High PYCR1 expression is associated with adverse clinical outcomes, and its knockdown inhibits tumor proliferation and metastasis, motivating inhibitor discovery. All structurally validated PYCR1 inhibitors to date bind in the active site and are anchored in the L-P5C binding pocket by an anionic functional group, typically carboxylate. Seeking inhibitors with alternative anchors, we used X-ray crystallography to screen 22 fragment-like compounds (MW = 189-343 Da) from docking that represent six different carboxylic acid isosteres. Surprisingly, only one compound bound in the active site. Four other compounds were found in three adjacent remote sites located in oligomer interfaces. The compounds bind 7 A from NADH and 10-14 A from L-P5C, and the intervening space is blocked by protein for inhibitors in Sites 1A/1B and open for inhibitors in Site 2. Together, the three binding sites define a ligand binding hot spot groove that spans 33 A. The remote binders inhibit PYCR1 activity with K values from the mixed model of inhibition of 32 muM to 2 mM. Co-crystal structures of PYCR1 with combinations of allosteric inhibitors, NADH, and L-P5C/proline analogs suggest the inhibitors can bind to the ternary PYCR1-L-P5C-NAD(P)H complex in addition to the free enzyme, consistent with a mixed mechanism of inhibition. The discovery of an allosteric inhibitor binding groove that accommodates multiple fragments heralds a new era of PYCR1 inhibitor design.

Serendipitous Discovery of an Allosteric Inhibitor Binding Groove in the Proline Biosynthetic Enzyme Pyrroline-5-Carboxylate Reductase 1 (PYCR1).,Meeks KR, Mattingly CJ, Nix JC, Chuk O, Protopopov MV, Tarkhanova OO, Tanner JJ Biochem J. 2026 Jan 22:BCJ20250278. doi: 10.1042/BCJ20250278. PMID:41569420<ref>PMID:41569420</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 9q45" style="background-color:#fffaf0;"></div>
== References ==
<references/>
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Meeks KR]]
[[Category: Tanner JJ]]