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

Author(s)

Santiago, Andre da Silva ^[1] ; Counago, Rafael M. ^{[1, 2]} ; Ramos, Priscila Zonzini ^[1] ; Godoi, Paulo H. C. ^[1] ; Massirer, Katlin B. ^{[1, 2]} ; Gileadi, Opher ^[3] ; Elkins, Jonathan M. ^{[3, 1]}

Affiliation

^[1] Univ Estadual Campinas, Struct Genom Consortium, Cidade Univ Zeferino Vaz, Av Dr Andre Tosello 550, BR-13083886 Campinas, SP - Brazil

^[2] Univ Estadual Campinas, CBMEG, Ctr Mol Biol & Genet Engn, Av Candido Rondon 400, BR-13083875 Campinas, SP - Brazil

^[3] Univ Oxford, Struct Genom Consortium, Old Rd Campus Res Bldg, Roosevelt Dr, Oxford OX3 7DQ - England

• Document type: Journal article
• Source: SCIENTIFIC REPORTS; v. 8, OCT 4 2018.
• Web of Science Citations: 1

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. (AU)

• FAPESP's process: 13/50724-5 - Protein Kinase Chemical Biology Center: supporting drug development through open-access research
• Grantee: Paulo Arruda
• Support Opportunities: Research Grants - Research Partnership for Technological Innovation - PITE