8DKG
Structure of PYCR1 Thr171Met variant complexed with NADH
Summary for 8DKG
| Entry DOI | 10.2210/pdb8dkg/pdb |
| Descriptor | Isoform 3 of Pyrroline-5-carboxylate reductase 1, mitochondrial, 1,4-DIHYDRONICOTINAMIDE ADENINE DINUCLEOTIDE, SULFATE ION, ... (4 entities in total) |
| Functional Keywords | amino-acid biosynthesis, oxidoreductase, proline biosynthesis |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 5 |
| Total formula weight | 174461.94 |
| Authors | Meeks, K.R.,Tanner, J.J. (deposition date: 2022-07-05, release date: 2023-02-08, Last modification date: 2023-10-25) |
| Primary citation | Daudu, O.I.,Meeks, K.R.,Zhang, L.,Seravalli, J.,Tanner, J.J.,Becker, D.F. Functional Impact of a Cancer-Related Variant in Human Delta 1 -Pyrroline-5-Carboxylate Reductase 1. Acs Omega, 8:3509-3519, 2023 Cited by PubMed Abstract: Pyrroline-5-carboxylate reductase (PYCR) is a proline biosynthetic enzyme that catalyzes the NAD(P)H-dependent reduction of Δ-pyrroline-5-carboxylate (P5C) to proline. Humans have three PYCR isoforms, with PYCR1 often upregulated in different types of cancers. Here, we studied the biochemical and structural properties of the Thr171Met variant of PYCR1, which is found in patients with malignant melanoma and lung adenocarcinoma. Although PYCR1 is strongly associated with cancer progression, characterization of a PYCR1 variant in cancer patients has not yet been reported. Thr171 is conserved in all three PYCR isozymes and is located near the P5C substrate binding site. We found that the amino acid replacement does not affect thermostability but has a profound effect on PYCR1 catalytic activity. The of the PYCR1 variant T171M is 100- to 200-fold lower than wild-type PYCR1 when P5C is the variable substrate, and 10- to 25-fold lower when NAD(P)H is varied. A 1.84 Å resolution X-ray crystal structure of T171M reveals that the Met side chain invades the P5C substrate binding site, suggesting that the catalytic defect is due to steric clash preventing P5C from achieving the optimal pose for hydride transfer from NAD(P)H. These results suggest that any impact on PYCR1 function associated with T171M in cancer does not derive from increased catalytic activity. PubMed: 36713721DOI: 10.1021/acsomega.2c07788 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.85 Å) |
Structure validation
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