PDBsum entry 3qa2

Transferase/transferase inhibitor

PDB id: 3qa2

Contents

Protein chain

297 a.a.

Ligands

SO4 ×3

XNA ×2

Waters ×8

PDB id:

3qa2

Name:

Transferase/transferase inhibitor

Title:

X-ray structure of ketohexokinase in complex with a pyrimidopyrimidine analog 2

Structure:

Ketohexokinase. Chain: a, b. Synonym: hepatic fructokinase. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: khk. Expressed in: escherichia coli. Expression_system_taxid: 562.

Resolution:

2.52Å R-factor: 0.198 R-free: 0.237

Authors:

M.C.Abad

Key ref:

B.E.Maryanoff et al. (2011). Inhibitors of Ketohexokinase: Discovery of Pyrimidinopyrimidines with Specific Substitution that Complements the ATP-Binding Site. Acs Med Chem Lett, 2, 538-543. PubMed id: 24900346 DOI: 10.1021/ml200070g

Date:

10-Jan-11 Release date: 18-Jan-12

Protein chains

P50053  (KHK_HUMAN) -  Ketohexokinase from Homo sapiens

Seq: 298 a.a.

Struc: 297 a.a.*

* PDB and UniProt seqs differ at 3 residue positions (black crosses)

Enzyme reactions

• Enzyme class: E.C.2.7.1.3 - ketohexokinase.
• Reaction: beta-D-fructose + ATP = beta-D-fructose 1-phosphate + ADP + H⁺

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

DOI no: 10.1021/ml200070g

Acs Med Chem Lett 2:538-543 (2011)

PubMed id: 24900346

Inhibitors of Ketohexokinase: Discovery of Pyrimidinopyrimidines with Specific Substitution that Complements the ATP-Binding Site.

B.E.Maryanoff, J.C.O'Neill, D.F.McComsey, S.C.Yabut, D.K.Luci, A.D.Jordan, J.A.Masucci, W.J.Jones, M.C.Abad, A.C.Gibbs, I.Petrounia.

ABSTRACT

Attenuation of fructose metabolism by the inhibition of ketohexokinase (KHK; fructokinase) should reduce body weight, free fatty acids, and triglycerides, thereby offering a novel approach to treat diabetes and obesity in response to modern diets. We have identified potent, selective inhibitors of human hepatic KHK within a series of pyrimidinopyrimidines (1). For example, 8, 38, and 47 exhibited KHK IC50 values of 12, 7, and 8 nM, respectively, and also showed potent cellular KHK inhibition (IC50 < 500 nM), which relates to their intrinsic potency vs KHK and their ability to penetrate cells. X-ray cocrystal structures of KHK complexes of 3, 8, and 47 revealed the important interactions within the enzyme's adenosine 5'-triphosphate (ATP)-binding pocket.