4M49

Lactate Dehydrogenase A in complex with a substituted pyrazine inhibitor compound 18


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.05 Å
  • R-Value Free: 0.224 
  • R-Value Work: 0.171 
  • R-Value Observed: 0.172 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 2.0 of the entry. See complete history


Literature

Identification of 2-amino-5-aryl-pyrazines as inhibitors of human lactate dehydrogenase.

Fauber, B.P.Dragovich, P.S.Chen, J.Corson, L.B.Ding, C.Z.Eigenbrot, C.Giannetti, A.M.Hunsaker, T.Labadie, S.Liu, Y.Liu, Y.Malek, S.Peterson, D.Pitts, K.Sideris, S.Ultsch, M.Vanderporten, E.Wang, J.Wei, B.Yen, I.Yue, Q.

(2013) Bioorg Med Chem Lett 23: 5533-5539

  • DOI: https://doi.org/10.1016/j.bmcl.2013.08.060
  • Primary Citation of Related Structures:  
    4M49

  • PubMed Abstract: 

    A 2-amino-5-aryl-pyrazine was identified as an inhibitor of human lactate dehydrogenase A (LDHA) via a biochemical screening campaign. Biochemical and biophysical experiments demonstrated that the compound specifically interacted with human LDHA. Structural variation of the screening hit resulted in improvements in LDHA biochemical inhibition and pharmacokinetic properties. A crystal structure of an improved compound bound to human LDHA was also obtained and it explained many of the observed structure-activity relationships.


  • Organizational Affiliation

    Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA. Electronic address: benjampf@gene.com.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
L-lactate dehydrogenase A chain
A, B, C, D
331Homo sapiensMutation(s): 0 
Gene Names: LDHAPIG19
EC: 1.1.1.27
UniProt & NIH Common Fund Data Resources
Find proteins for P00338 (Homo sapiens)
Explore P00338 
Go to UniProtKB:  P00338
PHAROS:  P00338
GTEx:  ENSG00000134333 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP00338
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 5 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
NAI
Query on NAI

Download Ideal Coordinates CCD File 
E [auth A],
I [auth B],
L [auth C],
P [auth D]
1,4-DIHYDRONICOTINAMIDE ADENINE DINUCLEOTIDE
C21 H29 N7 O14 P2
BOPGDPNILDQYTO-NNYOXOHSSA-N
22Y
Query on 22Y

Download Ideal Coordinates CCD File 
G [auth A],
N [auth C],
Q [auth D]
3-(5-amino-6-{[(1R)-1-phenylethyl]amino}pyrazin-2-yl)-4-chlorobenzoic acid
C19 H17 Cl N4 O2
NKUNTWSMUIPKSU-LLVKDONJSA-N
EPE
Query on EPE

Download Ideal Coordinates CCD File 
F [auth A],
J [auth B],
M [auth C]
4-(2-HYDROXYETHYL)-1-PIPERAZINE ETHANESULFONIC ACID
C8 H18 N2 O4 S
JKMHFZQWWAIEOD-UHFFFAOYSA-N
SO4
Query on SO4

Download Ideal Coordinates CCD File 
H [auth A],
O [auth C],
R [auth D]
SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
LAC
Query on LAC

Download Ideal Coordinates CCD File 
K [auth B]LACTIC ACID
C3 H6 O3
JVTAAEKCZFNVCJ-UWTATZPHSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
22Y Binding MOAD:  4M49 Kd: 5000 (nM) from 1 assay(s)
BindingDB:  4M49 Kd: 5000 (nM) from 1 assay(s)
IC50: 2000 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.05 Å
  • R-Value Free: 0.224 
  • R-Value Work: 0.171 
  • R-Value Observed: 0.172 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 168.379α = 90
b = 81.821β = 117.65
c = 120.665γ = 90
Software Package:
Software NamePurpose
BOSdata collection
PHASERphasing
PHENIXrefinement
HKL-2000data reduction
SCALEPACKdata scaling

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2013-09-04
    Type: Initial release
  • Version 1.1: 2013-10-02
    Changes: Database references
  • Version 1.2: 2023-09-20
    Changes: Data collection, Database references, Derived calculations, Refinement description
  • Version 2.0: 2023-11-15
    Changes: Atomic model, Data collection