5CR5

X-RAY CRYSTAL STRUCTURE AT 1.61A RESOLUTION OF HUMAN MITOCHONDRIAL BRANCHED CHAIN AMINOTRANSFERASE (BCATM) COMPLEXED WITH A BIPHENYL PYRROLIDINE ETHER COMPOUND AND AN INTERNAL ALDIMINE LINKED PLP COFACTOR.


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.61 Å
  • R-Value Free: 0.199 
  • R-Value Work: 0.168 
  • R-Value Observed: 0.170 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.1 of the entry. See complete history


Literature

Discovery, SAR, and X-ray Binding Mode Study of BCATm Inhibitors from a Novel DNA-Encoded Library.

Deng, H.Zhou, J.Sundersingh, F.S.Summerfield, J.Somers, D.Messer, J.A.Satz, A.L.Ancellin, N.Arico-Muendel, C.C.Sargent Bedard, K.L.Beljean, A.Belyanskaya, S.L.Bingham, R.Smith, S.E.Boursier, E.Carter, P.Centrella, P.A.Clark, M.A.Chung, C.W.Davie, C.P.Delorey, J.L.Ding, Y.Franklin, G.J.Grady, L.C.Herry, K.Hobbs, C.Kollmann, C.S.Morgan, B.A.Pothier Kaushansky, L.J.Zhou, Q.

(2015) ACS Med Chem Lett 6: 919-924

  • DOI: https://doi.org/10.1021/acsmedchemlett.5b00179
  • Primary Citation of Related Structures:  
    5CR5

  • PubMed Abstract: 

    As a potential target for obesity, human BCATm was screened against more than 14 billion DNA encoded compounds of distinct scaffolds followed by off-DNA synthesis and activity confirmation. As a consequence, several series of BCATm inhibitors were discovered. One representative compound (R)-3-((1-(5-bromothiophene-2-carbonyl)pyrrolidin-3-yl)oxy)-N-methyl-2'-(methylsulfonamido)-[1,1'-biphenyl]-4-carboxamide (15e) from a novel compound library synthesized via on-DNA Suzuki-Miyaura cross-coupling showed BCATm inhibitory activity with IC50 = 2.0 μM. A protein crystal structure of 15e revealed that it binds to BCATm within the catalytic site adjacent to the PLP cofactor. The identification of this novel inhibitor series plus the establishment of a BCATm protein structure provided a good starting point for future structure-based discovery of BCATm inhibitors.


  • Organizational Affiliation

    Platform Technology and Science, GlaxoSmithKline , 830 Winter Street, Waltham, Massachusetts 02451, United States.


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
EL1
Query on EL1

Download Ideal Coordinates CCD File 
D [auth A],
L [auth B]
3-({(3R)-1-[(5-bromothiophen-2-yl)carbonyl]pyrrolidin-3-yl}oxy)-N-methyl-2'-[(methylsulfonyl)amino]biphenyl-4-carboxamide
C24 H24 Br N3 O5 S2
YDBFEELXWGATBW-MRXNPFEDSA-N
PLP
Query on PLP

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

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

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

Download Ideal Coordinates CCD File 
E [auth A],
M [auth B]
CHLORIDE ION
Cl
VEXZGXHMUGYJMC-UHFFFAOYSA-M
Binding Affinity Annotations 
IDSourceBinding Affinity
EL1 BindingDB:  5CR5 IC50: min: 2000, max: 3900 (nM) from 2 assay(s)
Binding MOAD:  5CR5 IC50: 2000 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.61 Å
  • R-Value Free: 0.199 
  • R-Value Work: 0.168 
  • R-Value Observed: 0.170 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 69.55α = 90
b = 105.59β = 90
c = 107.05γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
Aimlessdata scaling
PDB_EXTRACTdata extraction
MOSFLMdata reduction

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

  • Released Date: 2015-08-12 
  • Deposition Author(s): Somers, D.O.

Revision History  (Full details and data files)

  • Version 1.0: 2015-08-12
    Type: Initial release
  • Version 1.1: 2015-09-02
    Changes: Database references