2BK5

Human Monoamine Oxidase B: I199F mutant in complex with isatin


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.83 Å
  • R-Value Free: 0.206 
  • R-Value Work: 0.185 
  • R-Value Observed: 0.186 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Demonstration of Isoleucine 199 as a Structural Determinant for the Selective Inhibition of Human Monoamine Oxidase B by Specific Reversible Inhibitors.

Hubalek, F.Binda, C.Khalil, A.Li, M.Mattevi, A.Castagnoli, N.Edmondson, D.E.

(2005) J Biol Chem 280: 15761

  • DOI: https://doi.org/10.1074/jbc.M500949200
  • Primary Citation of Related Structures:  
    2BK3, 2BK4, 2BK5

  • PubMed 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.


  • Organizational Affiliation

    Department of Biochemistry, Emory University, Atlanta, Georgia 30322, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
AMINE OXIDASE [FLAVIN-CONTAINING] B
A, B
520Homo sapiensMutation(s): 1 
EC: 1.4.3.4
Membrane Entity: Yes 
UniProt & NIH Common Fund Data Resources
Find proteins for P27338 (Homo sapiens)
Explore P27338 
Go to UniProtKB:  P27338
PHAROS:  P27338
GTEx:  ENSG00000069535 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP27338
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Binding Affinity Annotations 
IDSourceBinding Affinity
ISN BindingDB:  2BK5 Ki: min: 33, max: 6000 (nM) from 6 assay(s)
IC50: min: 7943, max: 3.68e+5 (nM) from 7 assay(s)
Binding MOAD:  2BK5 Ki: 3000 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.83 Å
  • R-Value Free: 0.206 
  • R-Value Work: 0.185 
  • R-Value Observed: 0.186 
  • Space Group: C 2 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 130.843α = 90
b = 221.99β = 90
c = 86.072γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
MOSFLMdata reduction
SCALAdata scaling
REFMACphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2005-02-14
    Type: Initial release
  • Version 1.1: 2011-08-10
    Changes: Atomic model, Database references, Derived calculations, Non-polymer description, Other, Structure summary, Version format compliance
  • Version 1.2: 2023-12-13
    Changes: Data collection, Database references, Derived calculations, Other, Refinement description