9dl6

Structure of proline utilization A complexed with piperidine-3-carboxylic acid

spinqualitylabelsall models 9dl6, resolution 1.42Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 9dl6 is a 2 chain structure with sequence from Sinorhizobium meliloti SM11. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.42Å Ligands: A1BDB, FAD, FMT, ID7, MG, NAD, PEG, PG4, PGE, SO4 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function F7X6I3_SINMM Oxidizes proline to glutamate for use as a carbon and nitrogen source.[PIRNR:PIRNR000197] Publication Abstract from PubMed The proline catabolic pathway consisting of proline dehydrogenase (PRODH) and L-glutamate-gamma-semialdehyde (GSAL) dehydrogenase (GSALDH) catalyzes the four-electron oxidation of L-proline to L-glutamate. Chemical probes to these enzymes are of interest for their role in cancer and inherited metabolic disease. Here, we report the results of a crystallographic fragment-screening campaign targeting both enzymes. A unique aspect of our approach is the screening of both enzymes simultaneously using crystals of the bifunctional PRODH-GSALDH enzyme, proline utilization A (PutA). A 288-fragment library from Zenobia was screened in crystallo in cocktails of six fragments. Validation X-ray crystallography with individual fragments identified seven crystal hits distributed in the PRODH active site, GSALDH aldehyde substrate-binding site, and GSALDH NAD(+) adenine-binding site. The fragment bound in the PRODH active site, 4-methoxybenzyl alcohol, is structurally distinct from all known PRODH inhibitors as it lacks an anionic anchor and stabilizes open conformations of the active site, motivating the study of eighteen analogs. In total, thirteen crystal structures with resolutions ranging from 1.32 A to 1.80 A were determined, resolving the poses and interactions of seven fragments from the Zenobia library and five analogs of 4-methoxybenzyl alcohol. These results expand the chemical space of probes targeting proline catabolic enzymes and provide new structural information for further inhibitor development. Crystallographic Fragment Screening of a Bifunctional Proline Catabolic Enzyme Reveals New Inhibitor Templates for Proline Dehydrogenase and L-Glutamate-gamma-semialdehyde Dehydrogenase.,Meeks KR, Bogner AN, Nix JC, Tanner JJ Molecules. 2024 Nov 16;29(22):5408. doi: 10.3390/molecules29225408. PMID:39598797 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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