1. Binding and structural analyses of potent inhibitors of the human Ca2+/calmodulin dependent protein kinase kinase 2 (CAMKK2) identified from a collection of commercially-available kinase inhibitors
- Author
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Rafael M. Couñago, David H. Drewry, Anita P. T. Salmazo, Katlin B. Massirer, Jonathan M. Elkins, Carrow I. Wells, Caio V. dos Reis, P.H.C. Godoi, A.M. Fala, Opher Gileadi, Roger Sartori, P.Z. Ramos, A.S. Santiago, and Gerson . S Profeta
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0301 basic medicine ,Molecular Conformation ,lcsh:Medicine ,Calcium-Calmodulin-Dependent Protein Kinase Kinase ,Molecular Dynamics Simulation ,Ligands ,Biochemistry ,Article ,03 medical and health sciences ,Structure-Activity Relationship ,0302 clinical medicine ,Drug Discovery ,Animals ,Humans ,Protein kinase A ,lcsh:Science ,CAMK ,Protein Kinase Inhibitors ,CAMKK2 ,Multidisciplinary ,Chemistry ,Kinase ,lcsh:R ,AMPK ,Isothermal titration calorimetry ,Small molecule ,Recombinant Proteins ,Molecular Docking Simulation ,030104 developmental biology ,Phosphorylation ,lcsh:Q ,Structural biology ,030217 neurology & neurosurgery ,Protein Binding - Abstract
Calcium/Calmodulin-dependent Protein Kinase Kinase 2 (CAMKK2) acts as a signaling hub, receiving signals from various regulatory pathways and decoding them via phosphorylation of downstream protein kinases - such as AMPK (AMP-activated protein kinase) and CAMK types I and IV. CAMKK2 relevance is highlighted by its constitutive activity being implicated in several human pathologies. However, at present, there are no selective small-molecule inhibitors available for this protein kinase. Moreover, CAMKK2 and its closest human homolog, CAMKK1, are thought to have overlapping biological roles. Here we present six new co-structures of potent ligands bound to CAMKK2 identified from a library of commercially-available kinase inhibitors. Enzyme assays confirmed that most of these compounds are equipotent inhibitors of both human CAMKKs and isothermal titration calorimetry (ITC) revealed that binding to some of these molecules to CAMKK2 is enthalpy driven. We expect our results to advance current efforts to discover small molecule kinase inhibitors selective to each human CAMKK.
- Published
- 2020
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