PDBsum entry 1ojb

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Oxidoreductase PDB id
Jmol PyMol
Protein chains
499 a.a. *
FAD-1LP ×2
Waters ×404
* Residue conservation analysis
Superseded by: 2xfu
PDB id:
Name: Oxidoreductase
Title: Human monoamine oxidase b in complex with tranylcypromine
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)
2.20Å     R-factor:   0.208     R-free:   0.249
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
08-Jul-03     Release date:   15-Aug-03    
Go to PROCHECK summary

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

 Enzyme reactions 
   Enzyme class: E.C.  - Monoamine oxidase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: RCH2NHR' + H2O + O2 = RCHO + R'NH2 + H2O2
+ H(2)O
+ O(2)
+ R'NH(2)
+ H(2)O(2)
      Cofactor: FAD
Bound ligand (Het Group name = FAD) corresponds exactly
Molecule diagrams generated from .mol files obtained from the KEGG ftp site


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.
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.  

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.  
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
19834914 O.Buneeva, O.Gnedenko, V.Zgoda, A.Kopylov, V.Glover, A.Ivanov, A.Medvedev, and A.Archakov (2010).
Isatin-binding proteins of rat and mouse brain: proteomic identification and optical biosensor validation.
  Proteomics, 10, 23-37.  
19651103 P.F.Fitzpatrick (2010).
Oxidation of amines by flavoproteins.
  Arch Biochem Biophys, 493, 13-25.  
19407342 A.Karytinos, F.Forneris, A.Profumo, G.Ciossani, E.Battaglioli, C.Binda, and A.Mattevi (2009).
A novel mammalian flavin-dependent histone demethylase.
  J Biol Chem, 284, 17775-17782.  
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.  
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.  
  18607080 D.B.Langley, D.M.Trambaiolo, A.P.Duff, D.M.Dooley, H.C.Freeman, and J.M.Guss (2008).
Complexes of the copper-containing amine oxidase from Arthrobacter globiformis with the inhibitors benzylhydrazine and tranylcypromine.
  Acta Crystallogr Sect F Struct Biol Cryst Commun, 64, 577-583.
PDB codes: 1w4n 1w5z
19053775 E.M.Milczek, D.Bonivento, C.Binda, A.Mattevi, I.A.McDonald, and D.E.Edmondson (2008).
Structural and mechanistic studies of mofegiline inhibition of recombinant human monoamine oxidase B.
  J Med Chem, 51, 8019-8026.
PDB code: 2vz2
18343668 F.Forneris, C.Binda, E.Battaglioli, and A.Mattevi (2008).
LSD1: oxidative chemistry for multifaceted functions in chromatin regulation.
  Trends Biochem Sci, 33, 181-189.  
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.  
  18323603 K.E.Atkin, R.Reiss, N.J.Turner, A.M.Brzozowski, and G.Grogan (2008).
Cloning, expression, purification, crystallization and preliminary X-ray diffraction analysis of variants of monoamine oxidase from Aspergillus niger.
  Acta Crystallogr Sect F Struct Biol Cryst Commun, 64, 182-185.  
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.  
18640844 S.Hruschka, T.C.Rosen, S.Yoshida, K.L.Kirk, R.Fröhlich, B.Wibbeling, and G.Haufe (2008).
Fluorinated phenylcyclopropylamines. Part 5: Effects of electron-withdrawing or -donating aryl substituents on the inhibition of monoamine oxidases A and B by 2-aryl-2-fluoro-cyclopropylamines.
  Bioorg Med Chem, 16, 7148-7166.  
18391214 S.Y.Son, J.Ma, Y.Kondou, M.Yoshimura, E.Yamashita, and T.Tsukihara (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.
PDB codes: 2z5x 2z5y
17521909 A.Fierro, M.Osorio-Olivares, B.K.Cassels, D.E.Edmondson, S.Sepúlveda-Boza, and M.Reyes-Parada (2007).
Human and rat monoamine oxidase-A are differentially inhibited by (S)-4-alkylthioamphetamine derivatives: insights from molecular modeling studies.
  Bioorg Med Chem, 15, 5198-5206.  
  19707325 A.Medvedev, O.Buneeva, and V.Glover (2007).
Biological targets for isatin and its analogues: Implications for therapy.
  Biologics, 1, 151-162.  
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.  
17542620 E.C.Ralph, J.S.Hirschi, M.A.Anderson, W.W.Cleland, D.A.Singleton, and P.F.Fitzpatrick (2007).
Insights into the mechanism of flavoprotein-catalyzed amine oxidation from nitrogen isotope effects on the reaction of N-methyltryptophan oxidase.
  Biochemistry, 46, 7655-7664.  
17551828 J.C.Shih (2007).
Monoamine oxidases: from tissue homogenates to transgenic mice.
  Neurochem Res, 32, 1757-1761.  
17401536 M.A.Akyüz, S.S.Erdem, and D.E.Edmondson (2007).
The aromatic cage in the active site of monoamine oxidase B: effect on the structural and electronic properties of bound benzylamine and p-nitrobenzylamine.
  J Neural Transm, 114, 693-698.  
16458520 A.A.Khalil, B.Davies, and N.Castagnoli (2006).
Isolation and characterization of a monoamine oxidase B selective inhibitor from tobacco smoke.
  Bioorg Med Chem, 14, 3392-3398.  
17193252 A.Carotti, C.Altomare, M.Catto, C.Gnerre, L.Summo, A.De Marco, S.Rose, P.Jenner, and B.Testa (2006).
Lipophilicity plays a major role in modulating the inhibition of monoamine oxidase B by 7-substituted coumarins.
  Chem Biodivers, 3, 134-149.  
16430210 A.Nagpal, M.P.Valley, P.F.Fitzpatrick, and A.M.Orville (2006).
Crystal structures of nitroalkane oxidase: insights into the reaction mechanism from a covalent complex of the flavoenzyme trapped during turnover.
  Biochemistry, 45, 1138-1150.
PDB codes: 2c0u 2c12
16914725 M.G.Lee, C.Wynder, D.A.Bochar, M.A.Hakimi, N.Cooch, and R.Shiekhattar (2006).
Functional interplay between histone demethylase and deacetylase enzymes.
  Mol Cell Biol, 26, 6395-6402.  
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.  
16467939 S.S.Erdem, O.Karahan, I.Yildiz, and K.Yelekçi (2006).
A computational study on the amine-oxidation mechanism of monoamine oxidase: insight into the polar nucleophilic mechanism.
  Org Biomol Chem, 4, 646-658.  
16366596 C.Binda, F.Hubálek, M.Li, Y.Herzig, J.Sterling, D.E.Edmondson, and A.Mattevi (2005).
Binding of rasagiline-related inhibitors to human monoamine oxidases: a kinetic and crystallographic analysis.
  J Med Chem, 48, 8148-8154.
PDB codes: 2c64 2c65 2c66 2c67
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
16079794 M.G.Lee, C.Wynder, N.Cooch, and R.Shiekhattar (2005).
An essential role for CoREST in nucleosomal histone 3 lysine 4 demethylation.
  Nature, 437, 432-435.  
14747710 J.Ma, F.Kubota, M.Yoshimura, E.Yamashita, A.Nakagawa, A.Ito, and T.Tsukihara (2004).
Crystallization and preliminary crystallographic analysis of rat monoamine oxidase A complexed with clorgyline.
  Acta Crystallogr D Biol Crystallogr, 60, 317-319.  
15272015 K.Chen, D.P.Holschneider, W.Wu, I.Rebrin, and J.C.Shih (2004).
A spontaneous point mutation produces monoamine oxidase A/B knock-out mice with greatly elevated monoamines and anxiety-like behavior.
  J Biol Chem, 279, 39645-39652.  
15300824 T.C.Rosen, S.Yoshida, K.L.Kirk, and G.Haufe (2004).
Fluorinated phenylcyclopropylamines as inhibitors of monoamine oxidases.
  Chembiochem, 5, 1033-1043.  
15223314 Z.Yang, L.Shipman, M.Zhang, B.P.Anton, R.J.Roberts, and X.Cheng (2004).
Structural characterization and comparative phylogenetic analysis of Escherichia coli HemK, a protein (N5)-glutamine methyltransferase.
  J Mol Biol, 340, 695-706.
PDB code: 1t43
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.