5T5T

AMPK bound to allosteric activator


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.46 Å
  • R-Value Free: 0.231 
  • R-Value Work: 0.211 
  • R-Value Observed: 0.212 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Selective Activation of AMPK beta 1-Containing Isoforms Improves Kidney Function in a Rat Model of Diabetic Nephropathy.

Salatto, C.T.Miller, R.A.Cameron, K.O.Cokorinos, E.Reyes, A.Ward, J.Calabrese, M.F.Kurumbail, R.G.Rajamohan, F.Kalgutkar, A.S.Tess, D.A.Shavnya, A.Genung, N.E.Edmonds, D.J.Jatkar, A.Maciejewski, B.S.Amaro, M.Gandhok, H.Monetti, M.Cialdea, K.Bollinger, E.Kreeger, J.M.Coskran, T.M.Opsahl, A.C.Boucher, G.G.Birnbaum, M.J.DaSilva-Jardine, P.Rolph, T.

(2017) J Pharmacol Exp Ther 361: 303-311

  • DOI: https://doi.org/10.1124/jpet.116.237925
  • Primary Citation of Related Structures:  
    5T5T

  • PubMed Abstract: 

    Diabetic nephropathy remains an area of high unmet medical need, with current therapies that slow down, but do not prevent, the progression of disease. A reduced phosphorylation state of adenosine monophosphate-activated protein kinase (AMPK) has been correlated with diminished kidney function in both humans and animal models of renal disease. Here, we describe the identification of novel, potent, small molecule activators of AMPK that selectively activate AMPK heterotrimers containing the β 1 subunit. After confirming that human and rodent kidney predominately express AMPK β 1, we explore the effects of pharmacological activation of AMPK in the ZSF1 rat model of diabetic nephropathy. Chronic administration of these direct activators elevates the phosphorylation of AMPK in the kidney, without impacting blood glucose levels, and reduces the progression of proteinuria to a greater degree than the current standard of care, angiotensin-converting enzyme inhibitor ramipril. Further analyses of urine biomarkers and kidney tissue gene expression reveal AMPK activation leads to the modulation of multiple pathways implicated in kidney injury, including cellular hypertrophy, fibrosis, and oxidative stress. These results support the need for further investigation into the potential beneficial effects of AMPK activation in kidney disease.


  • Organizational Affiliation

    CVMET Research Unit (C.T.S., R.A.M., E.C., A.R., J.W., A.J., B.S.M., M.A., H.G., M.M., K.C., E.B., M.J.B., P.D.-J., T.R.), Worldwide Medicinal Chemistry (K.O.C., D.J.E.), and Pharmacokinetics, Dynamics, & Metabolism (A.S.K., D.A.T.), Pfizer Worldwide Research and Development, Cambridge, Massachusetts; and Worldwide Medicinal Chemistry (M.C., R.K., F.R., A.S., N.E.G.), and Drug Safety Research and Development (J.M.K., T.M.C., A.C.O., G.G.B.), Pfizer Worldwide Research and Development, Groton, Connecticut christopher.t.salatto@pfizer.com.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
5'-AMP-activated protein kinase catalytic subunit alpha-1503Rattus norvegicusMutation(s): 0 
Gene Names: Prkaa1Ampk1
EC: 2.7.11.1 (PDB Primary Data), 2.7.11.27 (PDB Primary Data), 2.7.11.31 (PDB Primary Data), 2.7.11.26 (PDB Primary Data)
UniProt
Find proteins for P54645 (Rattus norvegicus)
Explore P54645 
Go to UniProtKB:  P54645
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP54645
Sequence Annotations
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  • Reference Sequence
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
5'-AMP-activated protein kinase subunit beta-1204Rattus norvegicusMutation(s): 2 
Gene Names: Prkab1
UniProt
Find proteins for P80386 (Rattus norvegicus)
Explore P80386 
Go to UniProtKB:  P80386
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP80386
Sequence Annotations
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  • Reference Sequence
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 3
MoleculeChains Sequence LengthOrganismDetailsImage
5'-AMP-activated protein kinase subunit gamma-1330Rattus norvegicusMutation(s): 0 
Gene Names: Prkag1
UniProt
Find proteins for P80385 (Rattus norvegicus)
Explore P80385 
Go to UniProtKB:  P80385
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP80385
Sequence Annotations
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  • Reference Sequence
Small Molecules
Ligands 6 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
STU
Query on STU

Download Ideal Coordinates CCD File 
D [auth A]STAUROSPORINE
C28 H26 N4 O3
HKSZLNNOFSGOKW-FYTWVXJKSA-N
ADP
Query on ADP

Download Ideal Coordinates CCD File 
L [auth C]ADENOSINE-5'-DIPHOSPHATE
C10 H15 N5 O10 P2
XTWYTFMLZFPYCI-KQYNXXCUSA-N
AMP
Query on AMP

Download Ideal Coordinates CCD File 
J [auth C],
K [auth C]
ADENOSINE MONOPHOSPHATE
C10 H14 N5 O7 P
UDMBCSSLTHHNCD-KQYNXXCUSA-N
75O
Query on 75O

Download Ideal Coordinates CCD File 
I [auth B]6-chloro-5-[6-(dimethylamino)-2-methoxypyridin-3-yl]-1H-indole-3-carboxylic acid
C17 H16 Cl N3 O3
MJHBRTGGZYSCHJ-UHFFFAOYSA-N
SO4
Query on SO4

Download Ideal Coordinates CCD File 
H [auth A],
M [auth C]
SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
CL
Query on CL

Download Ideal Coordinates CCD File 
E [auth A],
F [auth A],
G [auth A]
CHLORIDE ION
Cl
VEXZGXHMUGYJMC-UHFFFAOYSA-M
Modified Residues  1 Unique
IDChains TypeFormula2D DiagramParent
TPO
Query on TPO
A
L-PEPTIDE LINKINGC4 H10 N O6 PTHR
Binding Affinity Annotations 
IDSourceBinding Affinity
75O BindingDB:  5T5T Kd: 14 (nM) from 1 assay(s)
IC50: 420 (nM) from 1 assay(s)
EC50: min: 7, max: 4.00e+4 (nM) from 5 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.46 Å
  • R-Value Free: 0.231 
  • R-Value Work: 0.211 
  • R-Value Observed: 0.212 
  • Space Group: P 61 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 125.04α = 90
b = 125.04β = 90
c = 403.36γ = 120
Software Package:
Software NamePurpose
HKL-2000data scaling
PHASERphasing
BUSTER-TNTrefinement
PDB_EXTRACTdata extraction
HKL-2000data reduction
PHASERphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2017-03-29
    Type: Initial release
  • Version 1.1: 2017-04-26
    Changes: Database references
  • Version 1.2: 2023-10-04
    Changes: Data collection, Database references, Refinement description