5I5T

X-RAY CRYSTAL STRUCTURE AT 2.31A RESOLUTION OF HUMAN MITOCHONDRIAL BRANCHED CHAIN AMINOTRANSFERASE (BCATM) COMPLEXED WITH A TETRAHYDROQUINOLINE COMPOUND AND AN INTERNAL ALDIMINE LINKED PLP COFACTOR.


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.31 Å
  • R-Value Free: 0.235 
  • R-Value Work: 0.167 
  • R-Value Observed: 0.171 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.1 of the entry. See complete history


Literature

Structurally Diverse Mitochondrial Branched Chain Aminotransferase (BCATm) Leads with Varying Binding Modes Identified by Fragment Screening.

Borthwick, J.A.Ancellin, N.Bertrand, S.M.Bingham, R.P.Carter, P.S.Chung, C.W.Churcher, I.Dodic, N.Fournier, C.Francis, P.L.Hobbs, A.Jamieson, C.Pickett, S.D.Smith, S.E.Somers, D.O.Spitzfaden, C.Suckling, C.J.Young, R.J.

(2016) J Med Chem 59: 2452-2467

  • DOI: https://doi.org/10.1021/acs.jmedchem.5b01607
  • Primary Citation of Related Structures:  
    5I5S, 5I5T, 5I5U, 5I5V, 5I5W, 5I5X, 5I5Y, 5I60

  • PubMed Abstract: 

    Inhibitors of mitochondrial branched chain aminotransferase (BCATm), identified using fragment screening, are described. This was carried out using a combination of STD-NMR, thermal melt (Tm), and biochemical assays to identify compounds that bound to BCATm, which were subsequently progressed to X-ray crystallography, where a number of exemplars showed significant diversity in their binding modes. The hits identified were supplemented by searching and screening of additional analogues, which enabled the gathering of further X-ray data where the original hits had not produced liganded structures. The fragment hits were optimized using structure-based design, with some transfer of information between series, which enabled the identification of ligand efficient lead molecules with micromolar levels of inhibition, cellular activity, and good solubility.


  • Organizational Affiliation

    Medicines Research Centre, GlaxoSmithKline R&D , Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, U.K.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Branched-chain-amino-acid aminotransferase, mitochondrial
A, B
369Homo sapiensMutation(s): 0 
Gene Names: BCAT2BCATMBCT2ECA40
EC: 2.6.1.42
UniProt & NIH Common Fund Data Resources
Find proteins for O15382 (Homo sapiens)
Explore O15382 
Go to UniProtKB:  O15382
PHAROS:  O15382
GTEx:  ENSG00000105552 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupO15382
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 5 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
PLP
Query on PLP

Download Ideal Coordinates CCD File 
C [auth A],
L [auth B]
PYRIDOXAL-5'-PHOSPHATE
C8 H10 N O6 P
NGVDGCNFYWLIFO-UHFFFAOYSA-N
67X
Query on 67X

Download Ideal Coordinates CCD File 
D [auth A],
M [auth B]
(3R)-3-methyl-1,2,3,4-tetrahydroquinoline-8-sulfonamide
C10 H14 N2 O2 S
UVJPSTJAUUZEKC-SSDOTTSWSA-N
DMS
Query on DMS

Download Ideal Coordinates CCD File 
K [auth A]DIMETHYL SULFOXIDE
C2 H6 O S
IAZDPXIOMUYVGZ-UHFFFAOYSA-N
EDO
Query on EDO

Download Ideal Coordinates CCD File 
G [auth A]
H [auth A]
I [auth A]
J [auth A]
P [auth B]
G [auth A],
H [auth A],
I [auth A],
J [auth A],
P [auth B],
Q [auth B],
R [auth B]
1,2-ETHANEDIOL
C2 H6 O2
LYCAIKOWRPUZTN-UHFFFAOYSA-N
CL
Query on CL

Download Ideal Coordinates CCD File 
E [auth A],
F [auth A],
N [auth B],
O [auth B]
CHLORIDE ION
Cl
VEXZGXHMUGYJMC-UHFFFAOYSA-M
Binding Affinity Annotations 
IDSourceBinding Affinity
67X BindingDB:  5I5T IC50: 1.26e+6 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.31 Å
  • R-Value Free: 0.235 
  • R-Value Work: 0.167 
  • R-Value Observed: 0.171 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 69.03α = 90
b = 106.1β = 90
c = 107.798γ = 90
Software Package:
Software NamePurpose
SCALAdata scaling
REFMACrefinement
PDB_EXTRACTdata extraction
XDSdata reduction
REFMACphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

  • Released Date: 2016-03-23 
  • Deposition Author(s): Somers, D.O.

Revision History  (Full details and data files)

  • Version 1.0: 2016-03-23
    Type: Initial release
  • Version 1.1: 2016-04-06
    Changes: Database references