PDBsum entry 1ojc

Oxidoreductase

PDB id: 1ojc

Contents

Protein chain

499 a.a. *

Ligands

FAD-LAZ ×2

Waters ×416

* Residue conservation analysis

PDB id:

1ojc

Name:

Oxidoreductase

Title:

Human monoamine oxidase b in complex with n-(2-aminoethyl)-p- chlorobenzamide

Structure:

Amine oxidase [flavin-containing] b. Chain: a, b. Synonym: monoamine oxidase, mao-b. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: pichia pastoris. Expression_system_taxid: 4922

Biol. unit:

Dimer (from PDB file)

Resolution:

2.40Å R-factor: 0.194 R-free: 0.242

Authors:

C.Binda,D.E.Edmondson,A.Mattevi

Key ref:

C.Binda et al. (2003). Insights into the mode of inhibition of human mitochondrial monoamine oxidase B from high-resolution crystal structures. Proc Natl Acad Sci U S A, 100, 9750-9755. PubMed id: 12913124 DOI: 10.1073/pnas.1633804100

Date:

08-Jul-03 Release date: 15-Aug-03

Protein chains

P27338  (AOFB_HUMAN) -  Amine oxidase [flavin-containing] B from Homo sapiens

Seq: 520 a.a.

Struc: 499 a.a.

Enzyme reactions

• Enzyme class 2: E.C.1.4.3.21 - primary-amine oxidase.
• Reaction: a primary methyl amine + O2 + H2O = an aldehyde + H2O2 + NH4⁺
• Enzyme class 3: E.C.1.4.3.4 - monoamine oxidase.
• Reaction: a secondary aliphatic amine + O2 + H2O = a primary amine + an aldehyde + H2O2
• Cofactor: FAD

FAD (Bound ligand (Het Group name = FAD) corresponds exactly)

Note, where more than one E.C. class is given (as above), each may correspond to a different protein domain or, in the case of polyprotein precursors, to a different mature protein.

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

reference

DOI no: 10.1073/pnas.1633804100

Proc Natl Acad Sci U S A 100:9750-9755 (2003)

PubMed id: 12913124

Insights into the mode of inhibition of human mitochondrial monoamine oxidase B from high-resolution crystal structures.

C.Binda, M.Li, F.Hubalek, N.Restelli, D.E.Edmondson, A.Mattevi.

ABSTRACT

Monoamine oxidase B (MAO-B) is an outer mitochondrial membrane-bound enzyme that catalyzes the oxidative deamination of arylalkylamine neurotransmitters and has been a target for a number of clinically used drug inhibitors. The 1.7-A structure of the reversible isatin-MAO-B complex has been determined; it forms a basis for the interpretation of the enzyme's structure when bound to either reversible or irreversible inhibitors. 1,4-Diphenyl-2-butene is found to be a reversible MAO-B inhibitor, which occupies both the entrance and substrate cavity space in the enzyme. Comparison of these two structures identifies Ile-199 as a "gate" between the two cavities. Rotation of the side chain allows for either separation or fusion of the two cavities. Inhibition of the enzyme with N-(2-aminoethyl)-p-chlorobenzamide results in the formation of a covalent N(5) flavin adduct with the phenyl ring of the inhibitor occupying a position in the catalytic site overlapping that of isatin. Inhibition of MAO-B with the clinically used trans-2-phenylcyclopropylamine results in the formation of a covalent C(4a) flavin adduct with an opened cyclopropyl ring and the phenyl ring in a parallel orientation to the flavin. The peptide bond between the flavin-substituted Cys-397 and Tyr-398 is in a cis conformation, which allows the proper orientation of the phenolic ring of Tyr-398 in the active site. The flavin ring exists in a twisted nonplanar conformation, which is observed in the oxidized form as well as in both the N(5) and the C(4a) adducts. An immobile water molecule is H-bonded to Lys-296 and to the N(5) of the flavin as observed in other flavin-dependent amine oxidases. The active site cavities are highly apolar; however, hydrophilic areas exist near the flavin and direct the amine moiety of the substrate for binding and catalysis. Small conformational changes are observed on comparison of the different inhibitor-enzyme complexes. Future MAO-B drug design will need to consider "induced fit" contributions as an element in ligand-enzyme interactions.

Selected figure(s)

Figure 2.
Fig. 2. Structures of MAO-B inhibitors used in this study and atomic numbering of the flavin ring.

Figure 4.
Fig. 4. LIGPLOT (15) illustration of 1,4-diphenyl-2-butene binding to MAO-B. Dashed lines indicate H-bonds. Carbons are in black, nitrogens in blue, oxygens in red, and sulfurs in yellow. Water molecules are shown as cyan spheres.

Figures were selected by an automated process.