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PDBsum entry 2z5x

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Oxidoreductase PDB id
2z5x
Jmol
Contents
Protein chain
513 a.a. *
Ligands
FAD
HRM
DCX ×2
GOL ×3
Waters ×182
* Residue conservation analysis
PDB id:
2z5x
Name: Oxidoreductase
Title: Crystal structure of human monoamine oxidase a with harmine
Structure: Amine oxidase [flavin-containing] a. Chain: a. Fragment: residues 12-524. Synonym: monoamine oxidase type a, mao-a. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: saccharomyces cerevisiae. Expression_system_taxid: 4932.
Resolution:
2.20Å     R-factor:   0.204     R-free:   0.255
Authors: S.Y.Son,J.Ma,M.Yoshimura,T.Tsukihara
Key ref:
S.Y.Son et al. (2008). Structure of human monoamine oxidase A at 2.2-A resolution: the control of opening the entry for substrates/inhibitors. Proc Natl Acad Sci U S A, 105, 5739-5744. PubMed id: 18391214 DOI: 10.1073/pnas.0710626105
Date:
20-Jul-07     Release date:   01-Apr-08    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P21397  (AOFA_HUMAN) -  Amine oxidase [flavin-containing] A
Seq:
Struc:
 
Seq:
Struc:
527 a.a.
513 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   4 terms 
  Biological process     small molecule metabolic process   10 terms 
  Biochemical function     oxidoreductase activity     2 terms  

 

 
    reference    
 
 
DOI no: 10.1073/pnas.0710626105 Proc Natl Acad Sci U S A 105:5739-5744 (2008)
PubMed id: 18391214  
 
 
Structure of human monoamine oxidase A at 2.2-A resolution: the control of opening the entry for substrates/inhibitors.
S.Y.Son, J.Ma, Y.Kondou, M.Yoshimura, E.Yamashita, T.Tsukihara.
 
  ABSTRACT  
 
The mitochondrial outer membrane-anchored monoamine oxidase (MAO) is a biochemically important flavoenzyme that catalyzes the deamination of biogenic and xenobiotic amines. Its two subtypes, MAOA and MAOB, are linked to several psychiatric disorders and therefore are interesting targets for drug design. To understand the relationship between structure and function of this enzyme, we extended our previous low-resolution rat MAOA structure to the high-resolution wild-type and G110A mutant human MAOA structures at 2.2 and 2.17 A, respectively. The high-resolution MAOA structures are similar to those of rat MAOA and human MAOB, but different from the known structure of human MAOA [De Colibus L, et al. (2005) Proc Natl Acad Sci USA 102:12684-12689], specifically regarding residues 108-118 and 210-216, which surround the substrate/inhibitor cavity. The results confirm that the inhibitor selectivity of MAOA and MAOB is caused by the structural differences arising from Ile-335 in MAOA vs. Tyr-326 in MAOB. The structures exhibit a C-terminal transmembrane helix with clear electron density, as is also seen in rat MAOA. Mutations on one residue of loop 108-118, G110, which is far from the active center but close to the membrane surface, cause the solubilized enzyme to undergo a dramatic drop in activity, but have less effect when the enzyme is anchored in the membrane. These results suggest that the flexibility of loop 108-118, facilitated by anchoring the enzyme into the membrane, is essential for controlling substrate access to the active site. We report on the observation of the structure-function relationship between a transmembrane helical anchor and an extra-membrane domain.
 
  Selected figure(s)  
 
Figure 4.
Binding model of MAOA into the mitochondrial outer membrane. The positively charged residues Arg-129, His-148, Lys-151, Lys-163, Arg-493, Lys-503, Lys-520, and Lys-522 are shown. These residues are presumed to interact with the phospholipid hydrophilic head group at the membrane surface shown as blue semitransparent areas. The upper area represents the cytosolic side.
Figure 6.
Stereoviews of the substrate/inhibitor binding site. (A) The F [o] − F [c] difference Fourier map contoured at 2.0 σ was generated at 2.2-Å resolution for the inhibitor (harmine) and FAD. Amino acid residues are shown in yellow, and FAD and harmine are shown in green. Dotted lines indicate hydrogen bonds. (B) The structure of the substrate/inhibitor binding sites in human MAOA and MAOB complexed with specific inhibitors. The residues are numbered according to human MAOA, and the numbers in parentheses are for human MAOB. MAOA and MAOB residues are shown in yellow and light blue, respectively. Inhibitors are colored as follows: orange, harmine; green, isatin (PDB ID code 1OJA); purple, rasagiline analogue (PDB ID code 2C67); and red, 1,4-diphenyl-2-butene (PDB ID code 1OJ9). FAD is shown in black. Nitrogen and oxygen atoms are shown in blue and red, respectively. Residue I199 of MAOB is present as different rotamers in different complexes. The rotamer of this residue, in MAOB with 1,4-diphenyl-2-butene, is shown in red. The residues Q215 and Y407 that form important hydrophobic interactions to the inhibitors are shown as thick stick models.
 
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
  21442758 A.Gaspar, F.Teixeira, E.Uriarte, N.Milhazes, A.Melo, M.N.Cordeiro, F.Ortuso, S.Alcaro, and F.Borges (2011).
Towards the discovery of a novel class of monoamine oxidase inhibitors: structure-property-activity and docking studies on chromone amides.
  ChemMedChem, 6, 628-632.  
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.  
20673774 R.E.Hubbard (2011).
Structure-based drug discovery and protein targets in the CNS.
  Neuropharmacology, 60, 7.  
21397504 S.M.Shelke, S.H.Bhosale, R.C.Dash, M.R.Suryawanshi, and K.R.Mahadik (2011).
Exploration of new scaffolds as potential MAO-A inhibitors using pharmacophore and 3D-QSAR based in silico screening.
  Bioorg Med Chem Lett, 21, 2419-2424.  
21420424 Z.Zhou, L.Wang, Y.Gao, M.Wang, H.Zhang, L.Wang, L.Qiu, and L.Song (2011).
A monoamine oxidase from scallop Chlamys farreri serving as an immunomodulator in response against bacterial challenge.
  Dev Comp Immunol, 35, 799-807.  
20079438 B.K.Arslan, and D.E.Edmondson (2010).
Expression of zebrafish (Danio rerio) monoamine oxidase (MAO) in Pichia pastoris: purification and comparison with human MAO A and MAO B.
  Protein Expr Purif, 70, 290-297.  
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.  
20353187 M.S.Jorns, Z.W.Chen, and F.S.Mathews (2010).
Structural characterization of mutations at the oxygen activation site in monomeric sarcosine oxidase .
  Biochemistry, 49, 3631-3639.
PDB codes: 3m0o 3m12 3m13
20039094 R.Renthal (2010).
Helix insertion into bilayers and the evolution of membrane proteins.
  Cell Mol Life Sci, 67, 1077-1088.  
20480485 R.V.Dunn, A.W.Munro, N.J.Turner, S.E.Rigby, and N.S.Scrutton (2010).
Tyrosyl radical formation and propagation in flavin dependent monoamine oxidases.
  Chembiochem, 11, 1228-1231.  
20981014 Y.Ogawa, Y.Nonaka, T.Goto, E.Ohnishi, T.Hiramatsu, I.Kii, M.Yoshida, T.Ikura, H.Onogi, H.Shibuya, T.Hosoya, N.Ito, and M.Hagiwara (2010).
Development of a novel selective inhibitor of the Down syndrome-related kinase Dyrk1A.
  Nat Commun, 1, 1-9.
PDB codes: 3anq 3anr
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.  
18693755 G.Zhao, R.C.Bruckner, and M.S.Jorns (2008).
Identification of the oxygen activation site in monomeric sarcosine oxidase: role of Lys265 in catalysis.
  Biochemistry, 47, 9124-9135.  
18573102 R.V.Dunn, K.R.Marshall, A.W.Munro, and N.S.Scrutton (2008).
The pH dependence of kinetic isotope effects in monoamine oxidase A indicates stabilization of the neutral amine in the enzyme-substrate complex.
  FEBS J, 275, 3850-3858.  
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.