PDBsum entry 2c64

Oxidoreductase

PDB id: 2c64

Contents

Protein chain

499 a.a. *

Ligands

FAD

FAD-MA0

Waters ×293

* Residue conservation analysis

PDB id:

2c64

Name:

Oxidoreductase

Title:

Mao inhibition by rasagiline analogues

Structure:

Amine oxidase (flavin-containing) b. Chain: a, b. Synonym: monoamine oxidase b, 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:

2.20Å R-factor: 0.223 R-free: 0.260

Authors:

C.Binda,F.Hubalek,M.Li,Y.Herzig,J.Sterling,D.E.Edmondson,A.Mattevi

Key ref:

C.Binda et al. (2005). Binding of rasagiline-related inhibitors to human monoamine oxidases: a kinetic and crystallographic analysis. J Med Chem, 48, 8148-8154. PubMed id: 16366596 DOI: 10.1021/jm0506266

Date:

07-Nov-05 Release date: 04-Jan-06

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: 10.1021/jm0506266

J Med Chem 48:8148-8154 (2005)

PubMed id: 16366596

Binding of rasagiline-related inhibitors to human monoamine oxidases: a kinetic and crystallographic analysis.

C.Binda, F.Hubálek, M.Li, Y.Herzig, J.Sterling, D.E.Edmondson, A.Mattevi.

ABSTRACT

Monoamine oxidases A and B (MAO A and B) catalyze the degradation of neurotransmitters and represent drug targets for the treatment of neurodegenerative disorders. Rasagiline is an irreversible, MAO B-selective inhibitor that has been approved as a novel anti-Parkinson's drug. In this study, we investigate the inhibition of recombinant human MAO A and MAO B by several rasagiline analogues. Different substituents added onto the rasagiline scaffold alter the binding affinity depending on the position on the aminoindan ring and on the size of the substituent. Compounds with a hydroxyl group on either the C4 or the C6 atom inhibit both isozymes, whereas a bulkier substituent such as a carbamate is tolerated only at the C4 position. The 1.7 A crystal structure of MAO B in complex with 4-(N-methyl-N-ethyl-carbamoyloxy)-N-methyl-N-propargyl-1(R)-aminoindan shows that the binding mode is similar to that of rasagiline with the carbamate moiety occupying the entrance cavity space. 1(R)-Aminoindan, the major metabolic product of rasagiline, and its analogues reversibly inhibit both MAO A and MAO B. The crystal structure of N-methyl-1(R)-aminoindan bound to MAO B shows that its aminoindan ring adopts a different orientation compared to that of rasagiline.