7MWU
Structure of the E. coli PutA proline dehydrogenase domain (residues 86-630) complexed with cyclobutanecarboxylic acid
Summary for 7MWU
| Entry DOI | 10.2210/pdb7mwu/pdb |
| Descriptor | Bifunctional protein PutA, FLAVIN-ADENINE DINUCLEOTIDE, cyclobutanecarboxylic acid, ... (6 entities in total) |
| Functional Keywords | beta/alpha barrel, flavoenzyme, proline catabolism, oxidoreductase |
| Biological source | Escherichia coli |
| Total number of polymer chains | 1 |
| Total formula weight | 62725.22 |
| Authors | Tanner, J.J.,Bogner, A.N. (deposition date: 2021-05-17, release date: 2022-01-19, Last modification date: 2024-05-22) |
| Primary citation | Bogner, A.N.,Tanner, J.J. Structure-affinity relationships of reversible proline analog inhibitors targeting proline dehydrogenase. Org.Biomol.Chem., 20:895-905, 2022 Cited by PubMed Abstract: Proline dehydrogenase (PRODH) catalyzes the first step of proline catabolism, the FAD-dependent oxidation of L-proline to Δ-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, -(-)-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 (2)-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. PubMed: 35018940DOI: 10.1039/d1ob02328d PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.69 Å) |
Structure validation
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