9E0A
Structure of proline utilization A complexed with 1,4-benzenedimethanol
This is a non-PDB format compatible entry.
Summary for 9E0A
| Entry DOI | 10.2210/pdb9e0a/pdb |
| Descriptor | Bifunctional protein PutA, FLAVIN-ADENINE DINUCLEOTIDE, FORMIC ACID, ... (10 entities in total) |
| Functional Keywords | flavoenzyme, rossmann fold, proline dehydrogenase, aldehyde dehydrogenase, proline catabolism, substrate channeling, bifunctional enzyme, oxidoreductase |
| Biological source | Sinorhizobium meliloti |
| Total number of polymer chains | 2 |
| Total formula weight | 268145.00 |
| Authors | Tanner, J.J.,Meeks, K.R. (deposition date: 2024-10-17, release date: 2024-11-27, Last modification date: 2024-12-11) |
| Primary citation | Meeks, K.R.,Bogner, A.N.,Nix, J.C.,Tanner, J.J. Crystallographic Fragment Screening of a Bifunctional Proline Catabolic Enzyme Reveals New Inhibitor Templates for Proline Dehydrogenase and L-Glutamate-gamma-semialdehyde Dehydrogenase. Molecules, 29:-, 2024 Cited by PubMed Abstract: The proline catabolic pathway consisting of proline dehydrogenase (PRODH) and L-glutamate-γ-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 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 Å to 1.80 Å 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. PubMed: 39598797DOI: 10.3390/molecules29225408 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.39 Å) |
Structure validation
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