6E2M

ASK1 kinase domain complex with inhibitor


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.25 Å
  • R-Value Free: 0.259 
  • R-Value Work: 0.216 
  • R-Value Observed: 0.218 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.1 of the entry. See complete history


Literature

ASK1 contributes to fibrosis and dysfunction in models of kidney disease.

Liles, J.T.Corkey, B.K.Notte, G.T.Budas, G.R.Lansdon, E.B.Hinojosa-Kirschenbaum, F.Badal, S.S.Lee, M.Schultz, B.E.Wise, S.Pendem, S.Graupe, M.Castonguay, L.Koch, K.A.Wong, M.H.Papalia, G.A.French, D.M.Sullivan, T.Huntzicker, E.G.Ma, F.Y.Nikolic-Paterson, D.J.Altuhaifi, T.Yang, H.Fogo, A.B.Breckenridge, D.G.

(2018) J Clin Invest 128: 4485-4500

  • DOI: https://doi.org/10.1172/JCI99768
  • Primary Citation of Related Structures:  
    6E2M, 6E2N, 6E2O

  • PubMed Abstract: 

    Oxidative stress is an underlying component of acute and chronic kidney disease. Apoptosis signal-regulating kinase 1 (ASK1) is a widely expressed redox-sensitive serine threonine kinase that activates p38 and c-Jun N-terminal kinase (JNK) mitogen-activated protein kinase kinases, and induces apoptotic, inflammatory, and fibrotic signaling in settings of oxidative stress. We describe the discovery and characterization of a potent and selective small-molecule inhibitor of ASK1, GS-444217, and demonstrate the therapeutic potential of ASK1 inhibition to reduce kidney injury and fibrosis. Activation of the ASK1 pathway in glomerular and tubular compartments was confirmed in renal biopsies from patients with diabetic kidney disease (DKD) and was decreased by GS-444217 in several rodent models of kidney injury and fibrosis that collectively represented the hallmarks of DKD pathology. Treatment with GS-444217 reduced progressive inflammation and fibrosis in the kidney and halted glomerular filtration rate decline. Combination of GS-444217 with enalapril, an angiotensin-converting enzyme inhibitor, led to a greater reduction in proteinuria and regression of glomerulosclerosis. These results identify ASK1 as an important target for renal disease and support the clinical development of an ASK1 inhibitor for the treatment of DKD.


  • Organizational Affiliation

    Gilead Sciences, Foster City, California, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Mitogen-activated protein kinase kinase kinase 5
A, B
295Homo sapiensMutation(s): 0 
Gene Names: MAP3K5ASK1MAPKKK5MEKK5
EC: 2.7.11.25
UniProt & NIH Common Fund Data Resources
Find proteins for Q99683 (Homo sapiens)
Explore Q99683 
Go to UniProtKB:  Q99683
PHAROS:  Q99683
GTEx:  ENSG00000197442 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ99683
Sequence Annotations
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  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
KK7 (Subject of Investigation/LOI)
Query on KK7

Download Ideal Coordinates CCD File 
C [auth A],
D [auth B]
N-[3-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl]pyridine-2-carboxamide
C15 H13 N5 O
KMUXXLWWJGMJFW-UHFFFAOYSA-N
Modified Residues  1 Unique
IDChains TypeFormula2D DiagramParent
TPO
Query on TPO
A, B
L-PEPTIDE LINKINGC4 H10 N O6 PTHR
Binding Affinity Annotations 
IDSourceBinding Affinity
KK7 Binding MOAD:  6E2M IC50: 2200 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.25 Å
  • R-Value Free: 0.259 
  • R-Value Work: 0.216 
  • R-Value Observed: 0.218 
  • Space Group: P 2 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 40.482α = 90
b = 108.303β = 90
c = 156.83γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
HKL-2000data reduction
HKL-2000data scaling
PHENIXphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2018-09-19
    Type: Initial release
  • Version 1.1: 2018-10-17
    Changes: Data collection, Database references