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PDBsum entry 2bk3

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protein ligands Protein-protein interface(s) links
Oxidoreductase PDB id
2bk3
Jmol
Contents
Protein chain
499 a.a. *
Ligands
FAD ×2
FOH ×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    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P27338  (AOFB_HUMAN) -  Amine oxidase [flavin-containing] B
Seq:
Struc:
 
Seq:
Struc:
520 a.a.
499 a.a.
Key:    PfamA domain  PfamB domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.1.4.3.4  - Monoamine oxidase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: RCH2NHR' + H2O + O2 = RCHO + R'NH2 + H2O2
RCH(2)NHR'
+ H(2)O
+ O(2)
= RCHO
+ R'NH(2)
+ H(2)O(2)
      Cofactor: FAD
FAD
Bound ligand (Het Group name = FAD) corresponds exactly
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     membrane   6 terms 
  Biological process     small molecule metabolic process   14 terms 
  Biochemical function     electron carrier activity     5 terms  

 

 
    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.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21354322 M.Aldeco, B.K.Arslan, and D.E.Edmondson (2011).
Catalytic and inhibitor binding properties of zebrafish monoamine oxidase (zMAO): comparisons with human MAO A and MAO B.
  Comp Biochem Physiol B Biochem Mol Biol, 159, 78-83.  
19883764 J.Wang, and D.E.Edmondson (2010).
High-level expression and purification of rat monoamine oxidase A (MAO A) in Pichia pastoris: comparison with human MAO A.
  Protein Expr Purif, 70, 211-217.  
19296688 A.K.Upadhyay, and D.E.Edmondson (2009).
Development of spin-labeled pargyline analogues as specific inhibitors of human monoamine oxidases A and B.
  Biochemistry, 48, 3928-3935.  
19371079 D.E.Edmondson, C.Binda, J.Wang, A.K.Upadhyay, and A.Mattevi (2009).
Molecular and mechanistic properties of the membrane-bound mitochondrial monoamine oxidases.
  Biochemistry, 48, 4220-4230.  
19342233 E.M.Van der Walt, E.M.Milczek, S.F.Malan, D.E.Edmondson, N.Castagnoli, J.J.Bergh, and J.P.Petzer (2009).
Inhibition of monoamine oxidase by (E)-styrylisatin analogues.
  Bioorg Med Chem Lett, 19, 2509-2513.  
19645722 J.Wang, J.Harris, D.D.Mousseau, and D.E.Edmondson (2009).
Mutagenic probes of the role of Ser209 on the cavity shaping loop of human monoamine oxidase A.
  FEBS J, 276, 4569-4581.  
19673610 M.Naoi, and W.Maruyama (2009).
Functional mechanism of neuroprotection by inhibitors of type B monoamine oxidase in Parkinson's disease.
  Expert Rev Neurother, 9, 1233-1250.  
18424170 A.K.Upadhyay, and D.E.Edmondson (2008).
Characterization of detergent purified recombinant rat liver monoamine oxidase B expressed in Pichia pastoris.
  Protein Expr Purif, 59, 349-356.  
18065227 M.O.Ogunrombi, S.F.Malan, G.Terre'blanche, N.Castagnoli, J.J.Bergh, and J.P.Petzer (2008).
Structure-activity relationships in the inhibition of monoamine oxidase B by 1-methyl-3-phenylpyrroles.
  Bioorg Med Chem, 16, 2463-2472.  
17573034 D.E.Edmondson, C.Binda, and A.Mattevi (2007).
Structural insights into the mechanism of amine oxidation by monoamine oxidases A and B.
  Arch Biochem Biophys, 464, 269-276.  
17393064 D.E.Edmondson, L.DeColibus, C.Binda, M.Li, and A.Mattevi (2007).
New insights into the structures and functions of human monoamine oxidases A and B.
  J Neural Transm, 114, 703-705.  
17393065 F.Cruz, and D.E.Edmondson (2007).
Kinetic properties of recombinant MAO-A on incorporation into phospholipid nanodisks.
  J Neural Transm, 114, 699-702.  
17401533 K.Yelekçi, O.Karahan, and M.Toprakçi (2007).
Docking of novel reversible monoamine oxidase-B inhibitors: efficient prediction of ligand binding sites and estimation of inhibitors thermodynamic properties.
  J Neural Transm, 114, 725-732.  
17404836 Z.B.Ramadan, M.L.Wrang, and K.F.Tipton (2007).
Species differences in the selective inhibition of monoamine oxidase (1-methyl-2-phenylethyl)hydrazine and its potentiation by cyanide.
  Neurochem Res, 32, 1783-1790.  
16611214 F.Chimenti, A.Bolasco, F.Manna, D.Secci, P.Chimenti, A.Granese, O.Befani, P.Turini, S.Alcaro, and F.Ortuso (2006).
Synthesis and molecular modelling of novel substituted-4,5-dihydro-(1H)-pyrazole derivatives as potent and highly selective monoamine oxidase-A inhibitors.
  Chem Biol Drug Des, 67, 206-214.  
16552415 M.B.Youdim, D.Edmondson, and K.F.Tipton (2006).
The therapeutic potential of monoamine oxidase inhibitors.
  Nat Rev Neurosci, 7, 295-309.  
17124494 M.Kato, R.M.Wynn, J.L.Chuang, C.A.Brautigam, M.Custorio, and D.T.Chuang (2006).
A synchronized substrate-gating mechanism revealed by cubic-core structure of the bovine branched-chain alpha-ketoacid dehydrogenase complex.
  EMBO J, 25, 5983-5994.
PDB codes: 2ihw 2ii3 2ii4 2ii5
16442801 N.Vlok, S.F.Malan, N.Castagnoli, J.J.Bergh, and J.P.Petzer (2006).
Inhibition of monoamine oxidase B by analogues of the adenosine A2A receptor antagonist (E)-8-(3-chlorostyryl)caffeine (CSC).
  Bioorg Med Chem, 14, 3512-3521.  
16129825 L.De Colibus, M.Li, C.Binda, A.Lustig, D.E.Edmondson, and A.Mattevi (2005).
Three-dimensional structure of human monoamine oxidase A (MAO A): relation to the structures of rat MAO A and human MAO B.
  Proc Natl Acad Sci U S A, 102, 12684-12689.
PDB codes: 2bxr 2bxs 2byb
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB codes are shown on the right.