PDBsum entry 2bk3

Oxidoreductase

PDB id: 2bk3

Contents

Protein chain

499 a.a. *

Ligands

FAD ×2

FOF ×2

Waters ×384

* Residue conservation analysis

PDB id:

2bk3

Name:

Oxidoreductase

Title:

Human monoamine oxidase b in complex with farnesol

Structure:

Amine oxidase [flavin-containing] b. Chain: a, b. Synonym: human monoamine oxidase b, 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:

1.80Å R-factor: 0.226 R-free: 0.249

Authors:

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

Key ref:

F.Hubálek et al. (2005). Demonstration of isoleucine 199 as a structural determinant for the selective inhibition of human monoamine oxidase B by specific reversible inhibitors. J Biol Chem, 280, 15761-15766. PubMed id: 15710600 DOI: 10.1074/jbc.M500949200

Date:

10-Feb-05 Release date: 14-Feb-05

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: 10.1074/jbc.M500949200

J Biol Chem 280:15761-15766 (2005)

PubMed id: 15710600

Demonstration of isoleucine 199 as a structural determinant for the selective inhibition of human monoamine oxidase B by specific reversible inhibitors.

F.Hubálek, C.Binda, A.Khalil, M.Li, A.Mattevi, N.Castagnoli, D.E.Edmondson.

ABSTRACT

Several reversible inhibitors selective for human monoamine oxidase B (MAO B) that do not inhibit MAO A have been described in the literature. The following compounds: 8-(3-chlorostyryl)caffeine, 1,4-diphenyl-2-butene, and trans,trans-farnesol are shown to inhibit competitively human, horse, rat, and mouse MAO B with K(i) values in the low micromolar range but are without effect on either bovine or sheep MAO B or human MAO A. In contrast, the reversible competitive inhibitor isatin binds to all known MAO B and MAO A with similar affinities. Sequence alignments and the crystal structures of human MAO B in complex with 1,4-diphenyl-2-butene or with trans,trans-farnesol provide molecular insights into these specificities. These inhibitors span the substrate and entrance cavities with the side chain of Ile-199 rotated out of its normal conformation suggesting that Ile-199 is gating the substrate cavity. Ile-199 is conserved in all known MAO B sequences except bovine MAO B, which has Phe in this position (the sequence of sheep MAO B is unknown). Phe is conserved in the analogous position in MAO A sequences. The human MAO B I199F mutant protein of MAO B binds to isatin (K(i) = 3 microM) but not to the three inhibitors listed above. The crystal structure of this mutant demonstrates that the side chain of Phe-199 interferes with the binding of those compounds. This suggests that the Ile-199 "gate" is a determinant for the specificity of these MAO B inhibitors and provides a molecular basis for the development of MAO B-specific reversible inhibitors without interference with MAO A function in neurotransmitter metabolism.

Selected figure(s)

Figure 1.
FIG. 1. Schematic representation of the MAO B subunit in complex with trans,trans-farnesol. The FAD-binding domain is in blue, the substrate-binding domain in red, and the membrane-binding C-terminal region in green. The FAD cofactor and trans,trans-farnesol are shown as yellow and black ball-and-stick representations, respectively. The inhibitor-binding cavity is outlined by a cyan semitransparent surface.

Figure 2.
FIG. 2. Stereo plots of the complex between trans,trans-farnesol and wild-type MAO B. A, active site structure of the bound inhibitor and the conformation of Ile-199. B, close-up view of the position of bound trans,trans-farnesol with respect to the flavin ring. The dashed lines refer to the distances (3.4 Å) between the farnesol oxygen and the flavin C(4a) position and between the C(1) of farnesol and the flavin N(5) position.

The above figures are reprinted by permission from the ASBMB: J Biol Chem (2005, 280, 15761-15766) copyright 2005.

Figures were selected by an automated process.