9GNS

X-ray structure of Human holo aromatic L-amino acid decarboxylase (AADC) complex with Carbidopa at physiological pH

9GNS の概要

• エントリーDOI: 10.2210/pdb9gns/pdb
• 分子名称: Aromatic-L-amino-acid decarboxylase, PYRIDOXAL-5'-PHOSPHATE, CARBIDOPA, ... (5 entities in total)
• 機能のキーワード: dopa decarboxylase, ddc, aromatic l-amino acid decarboxylase, aadc, carbidopa, biosynthetic protein
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 54630.79

構造登録者

Perduca, M.,Bisello, G.,Bertoldi, M. (登録日: 2024-09-04, 公開日: 2025-05-14, 最終更新日: 2025-06-04)

主引用文献

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

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: 40401103
DOI: 10.1021/acscatal.5c00326

実験手法

X-RAY DIFFRACTION (1.93 Å)