PDBsum entry 1js3

Lyase

PDB id: 1js3

Contents

Protein chains

464 a.a. *

Ligands

SO4 ×4

PLP-142 ×2

Waters ×455

* Residue conservation analysis

PDB id:

1js3

Name:

Lyase

Title:

Crystal structure of dopa decarboxylase in complex with the inhibitor carbidopa

Structure:

Dopa decarboxylase. Chain: a, b. Synonym: aromatic-l-amino-acid decarboxylase. Ddc. Engineered: yes

Source:

Sus scrofa. Pig. Organism_taxid: 9823. Organ: kidney. Expressed in: escherichia coli. Expression_system_taxid: 562.

Biol. unit:

Dimer (from PQS)

Resolution:

2.25Å R-factor: 0.144 R-free: 0.187

Authors:

P.Burkhard,P.Dominici,C.Borri-Voltattorni,J.N.Jansonius, V.N.Malashkevich

Key ref:

P.Burkhard et al. (2001). Structural insight into Parkinson's disease treatment from drug-inhibited DOPA decarboxylase. Nat Struct Biol, 8, 963-967. PubMed id: 11685243 DOI: 10.1038/nsb1101-963

Date:

16-Aug-01 Release date: 26-Oct-01

Protein chains

P80041  (DDC_PIG) -  Aromatic-L-amino-acid decarboxylase from Sus scrofa

Seq: 486 a.a.

Struc: 464 a.a.

Enzyme reactions

• Enzyme class: E.C.4.1.1.28 - aromatic-L-amino-acid decarboxylase.
• Pathway: Dopa Biosynthesis
• Reaction:
  1. L-dopa + H⁺ = dopamine + CO2
  2. 5-hydroxy-L-tryptophan + H⁺ = serotonin + CO2

L-dopa + H(+) (Bound ligand (Het Group name = 142) matches with 87.50% similarity) = dopamine + CO2

5-hydroxy-L-tryptophan (Bound ligand (Het Group name = 142) matches with 68.42% similarity) + H(+) = serotonin + CO2

• Cofactor: Pyridoxal 5'-phosphate

Pyridoxal 5'-phosphate (Bound ligand (Het Group name = PLP) matches with 93.75% similarity)

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

DOI no: 10.1038/nsb1101-963

Nat Struct Biol 8:963-967 (2001)

PubMed id: 11685243

Structural insight into Parkinson's disease treatment from drug-inhibited DOPA decarboxylase.

P.Burkhard, P.Dominici, C.Borri-Voltattorni, J.N.Jansonius, V.N.Malashkevich.

ABSTRACT

DOPA decarboxylase (DDC) is responsible for the synthesis of the key neurotransmitters dopamine and serotonin via decarboxylation of L-3,4-dihydroxyphenylalanine (L-DOPA) and L-5-hydroxytryptophan, respectively. DDC has been implicated in a number of clinic disorders, including Parkinson's disease and hypertension. Peripheral inhibitors of DDC are currently used to treat these diseases. We present the crystal structures of ligand-free DDC and its complex with the anti-Parkinson drug carbiDOPA. The inhibitor is bound to the enzyme by forming a hydrazone linkage with the cofactor, and its catechol ring is deeply buried in the active site cleft. The structures provide the molecular basis for the development of new inhibitors of DDC with better pharmacological characteristics.

Selected figure(s)

Figure 2.
Figure 2. Stereo view ribbon diagram of the polypeptide backbone of DDC. The view is directly down the two-fold symmetry axis. One monomer is completely red, whereas the other is green (N-terminal domain), cyan (large domain) and blue (small domain). The cofactors (PLP) and the inhibitors (carbiDOPA) are shown in ball-and-stick representation in yellow. The N-terminal domain of one monomer packs on top of the other monomer, resulting in an extended dimer interface. The picture was drawn with MOLSCRIPT50 and RASTER3D^51.

Figure 3.
Figure 3. Active site cleft of DDC in complex with carbiDOPA. a, Stereo view of the electron density of the inhibitor carbiDOPA. The difference electron density (|F[o]| - |F[c]| map with the inhibitor excluded from the phase calculation) in red, contoured at 4 , is superimposed onto the inhibitor model. Nitrogen, phosphate and oxygen atoms are marked blue, cyan and red, respectively. Carbon atoms are colored in yellow for the enzyme, in magenta for the PLP -carbiDOPA complex and in orange for the residues of the other monomer. Hydrogen bonds are indicated in green dotted lines. b, Detailed view of the hydrogen bond interactions, including all structural water molecules in the active site. Color code as in (a). c, A model of modified carbiDOPA with an additional 2' hydroxyl group (cyan). The newly established hydrogen bonds to the structural water molecules and the hydrazone nitrogen are indicated as dotted lines (cyan). Otherwise, the color code is as in (a). The picture was drawn with MOLSCRIPT50 and RASTER3D^51.

The above figures are reprinted by permission from Macmillan Publishers Ltd: Nat Struct Biol (2001, 8, 963-967) copyright 2001.

Figures were selected by the author.