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Sci Rep. 2018 Oct 4;8(1):14800. doi: 10.1038/s41598-018-33043-4.

Structural Analysis of Inhibitor Binding to CAMKK1 Identifies Features Necessary for Design of Specific Inhibitors.

Author information

1
Structural Genomics Consortium, Universidade Estadual de Campinas, Cidade Universitária Zeferino Vaz, Av. Dr. André Tosello, 550, Barão Geraldo, Campinas, SP, 13083-886, Brazil.
2
Center for Molecular Biology and Genetic Engineering, CBMEG, University of Campinas, Av Candido Rondon, 400, Barao Geraldo, Campinas, SP, 13083-875, Brazil.
3
Structural Genomics Consortium, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford, OX3 7DQ, UK.
4
Structural Genomics Consortium, Universidade Estadual de Campinas, Cidade Universitária Zeferino Vaz, Av. Dr. André Tosello, 550, Barão Geraldo, Campinas, SP, 13083-886, Brazil. jon.elkins@sgc.ox.ac.uk.
5
Structural Genomics Consortium, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford, OX3 7DQ, UK. jon.elkins@sgc.ox.ac.uk.

Abstract

The calcium/calmodulin-dependent protein kinases (CAMKKs) are upstream activators of CAMK1 and CAMK4 signalling and have important functions in neural development, maintenance and signalling, as well as in other aspects of biology such as Ca2+ signalling in the cardiovascular system. To support the development of specific inhibitors of CAMKKs we have determined the crystal structure of CAMKK1 with two ATP-competitive inhibitors. The structures reveal small but exploitable differences between CAMKK1 and CAMKK2, despite the high sequence identity, which could be used in the generation of specific inhibitors. Screening of a kinase inhibitor library revealed molecules that bind potently to CAMKK1. Isothermal titration calorimetry revealed that the most potent inhibitors had binding energies largely dependent on favourable enthalpy. Together, the data provide a foundation for future inhibitor development activities.

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