3Q92

X-ray Structure of ketohexokinase in complex with a pyrimidopyrimidine analog 1

Summary for 3Q92

• Entry DOI: 10.2210/pdb3q92/pdb
• Related: 3NBV 3NBW 3NC2 3NC9 3NCA 3QA2 3QAI
• Descriptor: Ketohexokinase, N~8~-(cyclopropylmethyl)-N~4~-[2-(methylsulfanyl)phenyl]-2-(piperazin-1-yl)pyrimido[5,4-d]pyrimidine-4,8-diamine, SULFATE ION, ... (4 entities in total)
• Functional Keywords: ketohexokinase, atp binding, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 69286.46

Authors

Abad, M.C. (deposition date: 2011-01-07, release date: 2012-01-18, Last modification date: 2023-09-13)

Primary citation

Maryanoff, B.E.,O'Neill, J.C.,McComsey, D.F.,Yabut, S.C.,Luci, D.K.,Jordan, A.D.,Masucci, J.A.,Jones, W.J.,Abad, M.C.,Gibbs, A.C.,Petrounia, I.
Inhibitors of Ketohexokinase: Discovery of Pyrimidinopyrimidines with Specific Substitution that Complements the ATP-Binding Site.
ACS Med Chem Lett, 2:538-543, 2011

PubMed 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.

PubMed: 24900346
DOI: 10.1021/ml200070g

Experimental method

X-RAY DIFFRACTION (2.8 Å)