Journal
STRUCTURE
Volume 20, Issue 8, Pages 1300-1309Publisher
CELL PRESS
DOI: 10.1016/j.str.2012.05.002
Keywords
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Funding
- National Institute of Health [HL071818, HL086865, GM081655]
- U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences [DE-AC02-06CH11357]
- Michigan Technology Tri-Corridor [085P1000817]
- NRW Graduate School LIMES Chemical Biology
- German Research Council (DFG) [Ma 3442/1-2]
- [DK20572]
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Cardiovascular homeostasis is maintained in part by the rapid desensitization of activated heptahelical receptors that have been phosphorylated by G protein-coupled receptor kinase 2 (GRK2). However, during chronic heart failure GRK2 is upregulated and believed to contribute to disease progression. We have determined crystallographic structures of GRK2 bound to an RNA aptamer that potently and selectively inhibits kinase activity. Key to the mechanism of inhibition is the positioning of an adenine nucleotide into the ATP-binding pocket and interactions with the basic alpha F-alpha G loop region of the GRK2 kinase domain. Constraints imposed on the RNA by the terminal stem of the aptamer also play a role. These results highlight how a high-affinity aptamer can be used to selectively trap a novel conformational state of a protein kinase.
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