9DUI
Re-refined of Crystal structure of dopa decarboxylase in complex with the inhibitor carbidopa (1JS3) with ketoenamine form of carbidopa
This is a non-PDB format compatible entry.
Summary for 9DUI
| Entry DOI | 10.2210/pdb9dui/pdb |
| Related | 1JS6 |
| Descriptor | Aromatic-L-amino-acid decarboxylase, (2S)-3-(3,4-dihydroxyphenyl)-2-[(2E)-2-({3-hydroxy-2-methyl-5-[(phosphonooxy)methyl]pyridin-4-yl}methylidene)hydrazin-1-yl]-2-methylpropanoic acid, SULFATE ION, ... (4 entities in total) |
| Functional Keywords | dopa decarboxylase, carbidopa, parkinson's disease, vitamin b6, lyase |
| Biological source | Sus scrofa (pig) |
| Total number of polymer chains | 2 |
| Total formula weight | 109351.39 |
| Authors | |
| Primary citation | Baine, J.M.,Duhoo, Y.,Doukov, T.,Desfosses, A.,Bisello, G.,Beio, M.L.,Bauer, O.,Perduca, M.,Bacia-Verloop, M.,Bertoldi, M.,Phillips, R.S.,Gutsche, I.,Berkowitz, D.B. alpha-Hydrazino Acids Inhibit Pyridoxal Phosphate-Dependent Decarboxylases via "Catalytically Correct" Ketoenamine Tautomers: A Special Motif for Chemical Biology and Drug Discovery? Acs Catalysis, 15:8204-8218, 2025 Cited by PubMed Abstract: We present evidence that supports a 'correct hydrazone tautomer/Dunathan alignment model' for how α-hydrazino analogues of α-amino acids inhibit PLP enzymes. Described is the asymmetric synthesis of l- and d-α-hydrazino acid l-lysine analogues and their inhibition of lysine decarboxylase (LdcI) via kinetic analysis, stopped-flow spectrophotometry, and cryo-EM. We describe a similar investigation of the important anti-Parkinsonism drug, carbidopa, with its human DOPA decarboxylase (hDdc) target. Evidence is consistent with these three hydrazino analogues forming the catalytically relevant ketoenamine PLP-hydrazone tautomer in their target active sites, with the α-carboxylate groups, though insulated, aligning with the PLP-π-system in a Dunathan-model-like orientation. High-resolution cryo-EM structures of the LdcI holoenzyme (pdb 9E0M-2.1Å) and LdcI-bound l- and d-hydrazones (pdb 9E0O-2.0 Å; pdb 9E0Q-2.3Å) and the first X-ray crystal structure of hDdc-bound carbidopa (pdb 9GNS-1.93Å) support this 'correct tautomer' model. These insights are expected to guide future PLP enzyme inhibitor development. PubMed: 40401103DOI: 10.1021/acscatal.5c00326 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.25 Å) |
Structure validation
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