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

DOI: 10.1038/s41598-019-52795-1

Authors: Gerson S. Profeta (Structural Genomics Consortium, Universidade Estadual de Campinas (UNICAMP)) , Caio V. Dos Reis (Structural Genomics Consortium, Universidade Estadual de Campinas (UNICAMP)) , André Da S. Santiago (Structural Genomics Consortium, Universidade Estadual de Campinas (UNICAMP)) , Paulo H. C. Godoi (Structural Genomics Consortium, Universidade Estadual de Campinas (UNICAMP)) , Angela M. Fala (Structural Genomics Consortium, Universidade Estadual de Campinas (UNICAMP)) , Carrow I. Wells (University of North Carolina at Chapel Hill) , Roger Sartori (Structural Genomics Consortium, Universidade Estadual de Campinas (UNICAMP)) , Anita P. T. Salmazo (Structural Genomics Consortium, Universidade Estadual de Campinas (UNICAMP)) , Priscila Z. Ramos (Structural Genomics Consortium, Universidade Estadual de Campinas (UNICAMP)) , Katlin B. Massirer (Structural Genomics Consortium, Universidade Estadual de Campinas (UNICAMP)) , Jonathan M. Elkins (Structural Genomics Consortium, Universidade Estadual de Campinas (UNICAMP)) , David H. Drewry (University of North Carolina at Chapel Hill) , Opher Gileadi (University of Oxford) , Rafael M. Counago (Structural Genomics Consortium, Universidade Estadual de Campinas (UNICAMP))
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Scientific Reports , VOL 9

State: Published (Approved)
Published: November 2019
Diamond Proposal Number(s): 16171

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.

Diamond Keywords: Enzymes

Subject Areas: Biology and Bio-materials, Chemistry, Medicine


Instruments: I24-Microfocus Macromolecular Crystallography

Other Facilities: Advanced Photon Source

Added On: 18/11/2019 14:30

Documents:
s41598-019-52795-1.pdf

Discipline Tags:

Health & Wellbeing Biochemistry Chemistry Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)