7mwu
From Proteopedia
(Difference between revisions)
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==Structure of the E. coli PutA proline dehydrogenase domain (residues 86-630) complexed with cyclobutanecarboxylic acid== | ==Structure of the E. coli PutA proline dehydrogenase domain (residues 86-630) complexed with cyclobutanecarboxylic acid== | ||
| - | <StructureSection load='7mwu' size='340' side='right'caption='[[7mwu]]' scene=''> | + | <StructureSection load='7mwu' size='340' side='right'caption='[[7mwu]], [[Resolution|resolution]] 1.69Å' scene=''> |
== Structural highlights == | == Structural highlights == | ||
| - | <table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7MWU OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7MWU FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[7mwu]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7MWU OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7MWU FirstGlance]. <br> |
| - | </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=7mwu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7mwu OCA], [https://pdbe.org/7mwu PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7mwu RCSB], [https://www.ebi.ac.uk/pdbsum/7mwu PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7mwu 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=1PE:PENTAETHYLENE+GLYCOL'>1PE</scene>, <scene name='pdbligand=FAD:FLAVIN-ADENINE+DINUCLEOTIDE'>FAD</scene>, <scene name='pdbligand=PGE:TRIETHYLENE+GLYCOL'>PGE</scene>, <scene name='pdbligand=ZPM:cyclobutanecarboxylic+acid'>ZPM</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=7mwu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7mwu OCA], [https://pdbe.org/7mwu PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7mwu RCSB], [https://www.ebi.ac.uk/pdbsum/7mwu PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7mwu ProSAT]</span></td></tr> | ||
</table> | </table> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | Proline dehydrogenase (PRODH) catalyzes the first step of proline catabolism, the FAD-dependent oxidation of L-proline to Delta(1)-pyrroline-5-carboxylate. PRODH plays a central role in the metabolic rewiring of cancer cells, which has motivated the discovery of inhibitors. Here, we studied the inhibition of PRODH by 18 proline-like compounds to understand the structural and chemical features responsible for the affinity of the best-known inhibitor, S-(-)-tetrahydro-2-furoic acid (1). The compounds were screened, and then six were selected for more thorough kinetic analysis: cyclobutane-1,1-dicarboxylic acid (2), cyclobutanecarboxylic acid (3), cyclopropanecarboxylic acid (4), cyclopentanecarboxylic acid (16), 2-oxobutyric acid (17), and (2S)-oxetane-2-carboxylic acid (18). These compounds are competitive inhibitors with inhibition constants in the range of 1.4-6 mM, compared to 0.3 mM for 1. Crystal structures of PRODH complexed with 2, 3, 4, and 18 were determined. All four inhibitors bind in the proline substrate site, but the orientations of their rings differ from that of 1. The binding of 3 and 18 is accompanied by compression of the active site to enable nonpolar contacts with Leu513. Compound 2 is unique in that the additional carboxylate displaces a structurally conserved water molecule from the active site. Compound 18 also destabilizes the conserved water, but by an unexpected non-steric mechanism. The results are interpreted using a chemical double mutant thermodynamic cycle. This analysis revealed unanticipated synergism between ring size and hydrogen bonding to the conserved water. These structure-affinity relationships provide new information relevant to the development of new inhibitor design strategies targeting PRODH. | ||
| + | |||
| + | Structure-affinity relationships of reversible proline analog inhibitors targeting proline dehydrogenase.,Bogner AN, Tanner JJ Org Biomol Chem. 2022 Jan 26;20(4):895-905. doi: 10.1039/d1ob02328d. PMID:35018940<ref>PMID:35018940</ref> | ||
| + | |||
| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
| + | <div class="pdbe-citations 7mwu" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
| - | [[Category: Bogner | + | [[Category: Bogner, A N]] |
| - | [[Category: Tanner | + | [[Category: Tanner, J J]] |
| + | [[Category: Beta/alpha barrel]] | ||
| + | [[Category: Flavoenzyme]] | ||
| + | [[Category: Oxidoreductase]] | ||
| + | [[Category: Proline catabolism]] | ||
Revision as of 07:12, 2 February 2022
Structure of the E. coli PutA proline dehydrogenase domain (residues 86-630) complexed with cyclobutanecarboxylic acid
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