PDBsum entry 3imx

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Transferase PDB id
Protein chain
447 a.a. *
Waters ×276
* Residue conservation analysis
PDB id:
Name: Transferase
Title: Crystal structure of human glucokinase in complex with a synthetic activator
Structure: Glucokinase. Chain: a. Fragment: residues 16-465. Synonym: hexokinase 4, maturity onset diabetes of the young 2, isoform cra_b. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: gck, hcg_1745191, tcag7.801. Expressed in: escherichia coli. Expression_system_taxid: 562.
2.00Å     R-factor:   0.195     R-free:   0.245
Authors: T.Stams,B.Vash
Key ref: G.R.Bebernitz et al. (2009). Investigation of functionally liver selective glucokinase activators for the treatment of type 2 diabetes. J Med Chem, 52, 6142-6152. PubMed id: 19746978 DOI: 10.1021/jm900839k
11-Aug-09     Release date:   06-Oct-09    
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Protein chain
Pfam   ArchSchema ?
P35557  (HXK4_HUMAN) -  Glucokinase
465 a.a.
447 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 5 residue positions (black crosses)

 Enzyme reactions 
   Enzyme class: E.C.  - Glucokinase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: ATP + D-glucose = ADP + D-glucose 6-phosphate
Bound ligand (Het Group name = GLC)
corresponds exactly
+ D-glucose 6-phosphate
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     cytoplasm   7 terms 
  Biological process     metabolic process   35 terms 
  Biochemical function     catalytic activity     15 terms  


DOI no: 10.1021/jm900839k J Med Chem 52:6142-6152 (2009)
PubMed id: 19746978  
Investigation of functionally liver selective glucokinase activators for the treatment of type 2 diabetes.
G.R.Bebernitz, V.Beaulieu, B.A.Dale, R.Deacon, A.Duttaroy, J.Gao, M.S.Grondine, R.C.Gupta, M.Kakmak, M.Kavana, L.C.Kirman, J.Liang, W.M.Maniara, S.Munshi, S.S.Nadkarni, H.F.Schuster, T.Stams, I.St Denny, P.M.Taslimi, B.Vash, S.L.Caplan.
Type 2 diabetes is a polygenic disease which afflicts nearly 200 million people worldwide and is expected to increase to near epidemic levels over the next 10-15 years. Glucokinase (GK) activators are currently under investigation by a number of pharmaceutical companies with only a few reaching early clinical evaluation. A GK activator has the promise of potentially affecting both the beta-cells of the pancreas, by improving glucose sensitive insulin secretion, as well as the liver, by reducing uncontrolled glucose output and restoring post-prandial glucose uptake and storage as glycogen. Herein, we report our efforts on a sulfonamide chemotype with the aim to generate liver selective GK activators which culminated in the discovery of 3-cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide (17c). This compound activated the GK enzyme (alphaK(a) = 39 nM) in vitro at low nanomolar concentrations and significantly reduced glucose levels during an oral glucose tolerance test in normal mice.

Literature references that cite this PDB file's key reference

  PubMed id Reference
21183342 J.A.Pfefferkorn, J.Litchfield, R.Hutchings, X.M.Cheng, S.D.Larsen, B.Auerbach, M.R.Bush, C.Lee, N.Erasga, D.M.Bowles, D.C.Boyles, G.Lu, C.Sekerke, V.Askew, J.C.Hanselman, L.Dillon, Z.Lin, A.Robertson, K.Olsen, C.Boustany, K.Atkinson, T.C.Goosen, V.Sahasrabudhe, J.Chupka, D.B.Duignan, B.Feng, R.Scialis, E.Kimoto, Y.A.Bi, Y.Lai, A.El-Kattan, R.Bakker-Arkema, P.Barclay, E.Kindt, V.Le, J.W.Mandema, M.Milad, B.D.Tait, R.Kennedy, B.K.Trivedi, and M.Kowala (2011).
Discovery of novel hepatoselective HMG-CoA reductase inhibitors for treating hypercholesterolemia: a bench-to-bedside case study on tissue selective drug distribution.
  Bioorg Med Chem Lett, 21, 2725-2731.  
21280170 M.L.Massa, J.J.Gagliardino, and F.Francini (2011).
Liver glucokinase: An overview on the regulatory mechanisms of its activity.
  IUBMB Life, 63, 1-6.  
21524589 P.McCarren, G.R.Bebernitz, P.Gedeck, S.Glowienke, M.S.Grondine, L.C.Kirman, J.Klickstein, H.F.Schuster, and L.Whitehead (2011).
Avoidance of the Ames test liability for aryl-amines via computation.
  Bioorg Med Chem, 19, 3173-3182.  
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