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PDBsum entry 3imx

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protein ligands metals links
Transferase PDB id
3imx
Jmol
Contents
Protein chain
447 a.a. *
Ligands
GLC
B84
Metals
_NA
Waters ×276
* Residue conservation analysis
PDB id:
3imx
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.
Resolution:
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
Date:
11-Aug-09     Release date:   06-Oct-09    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P35557  (HXK4_HUMAN) -  Glucokinase
Seq:
Struc:
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.2.7.1.2  - Glucokinase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: ATP + D-glucose = ADP + D-glucose 6-phosphate
ATP
+
D-glucose
Bound ligand (Het Group name = GLC)
corresponds exactly
= ADP
+ 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  

 

 
    reference    
 
 
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.
 
  ABSTRACT  
 
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.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time.