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PDBsum entry 2c66

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protein ligands Protein-protein interface(s) links
Oxidoreductase PDB id
2c66
Jmol PyMol
Contents
Protein chain
499 a.a. *
Ligands
FAD-RM2 ×2
Waters ×189
* Residue conservation analysis
PDB id:
2c66
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:
2.50Å     R-factor:   0.217     R-free:   0.285
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    
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   7 terms 
  Biological process     oxidation-reduction process   15 terms 
  Biochemical function     electron carrier activity     5 terms  

 

 
    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.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
20919927 O.Weinreb, O.Bar-Am, K.Prosolovich, T.Amit, and M.B.Youdim (2011).
Does 1-(R)-aminoindan Possess Neuroprotective Properties Against Experimental Parkinson's Disease?
  Antioxid Redox Signal, 14, 767-775.  
20002521 O.Bar-Am, O.Weinreb, T.Amit, and M.B.Youdim (2010).
The neuroprotective mechanism of 1-(R)-aminoindan, the major metabolite of the anti-parkinsonian drug rasagiline.
  J Neurochem, 112, 1131-1137.  
20600573 O.Weinreb, T.Amit, O.Bar-Am, and M.B.Youdim (2010).
Rasagiline: a novel anti-Parkinsonian monoamine oxidase-B inhibitor with neuroprotective activity.
  Prog Neurobiol, 92, 330-344.  
20410615 Z.Jia, S.Wei, and Q.Zhu (2010).
Monoamine oxidase inhibitors: benzylidene-prop-2-ynyl-amines analogues.
  Biol Pharm Bull, 33, 725-728.  
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.  
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
18183391 E.W.van Hellemond, M.van Dijk, D.P.Heuts, D.B.Janssen, and M.W.Fraaije (2008).
Discovery and characterization of a putrescine oxidase from Rhodococcus erythropolis NCIMB 11540.
  Appl Microbiol Biotechnol, 78, 455-463.  
18426222 T.A.White, W.H.Johnson, C.P.Whitman, and J.J.Tanner (2008).
Structural basis for the inactivation of Thermus thermophilus proline dehydrogenase by N-propargylglycine.
  Biochemistry, 47, 5573-5580.
PDB code: 2ekg
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.  
17511474 L.M.Szewczuk, J.C.Culhane, M.Yang, A.Majumdar, H.Yu, and P.A.Cole (2007).
Mechanistic analysis of a suicide inactivator of histone demethylase LSD1.
  Biochemistry, 46, 6892-6902.  
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.

 

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