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Molecular mechanism for inhibition of g protein-coupled receptor kinase 2 by a selective RNA aptamer.

Tesmer VM, Lennarz S, Mayer G, Tesmer JJ
Structure 20 1300-9 (2012)
Cited: 39 times
EuropePMC logo PMID: 22727813

Abstract

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 αF-αG 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.

Reviews - 3uzs mentioned but not cited (2)

  1. Structural insights into G protein-coupled receptor kinase function. Homan KT, Tesmer JJ. Curr Opin Cell Biol 27 25-31 (2014)
  2. Structural Biology for the Molecular Insight between Aptamers and Target Proteins. Zhang N, Chen Z, Liu D, Jiang H, Zhang ZK, Lu A, Zhang BT, Yu Y, Zhang G. Int J Mol Sci 22 4093 (2021)

Articles - 3uzs mentioned but not cited (3)



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  1. Embracing proteins: structural themes in aptamer-protein complexes. Gelinas AD, Davies DR, Janjic N. Curr Opin Struct Biol 36 122-132 (2016)
  2. Investigations on the interface of nucleic acid aptamers and binding targets. Cai S, Yan J, Xiong H, Liu Y, Peng D, Liu Z. Analyst 143 5317-5338 (2018)
  3. Current progress of aptamer-based molecular imaging. Wang AZ, Farokhzad OC. J Nucl Med 55 353-356 (2014)
  4. Progress in aptamer-mediated drug delivery vehicles for cancer targeting and its implications in addressing chemotherapeutic challenges. Zhu J, Huang H, Dong S, Ge L, Zhang Y. Theranostics 4 931-944 (2014)
  5. Recent applications of the combination of mesoporous silica nanoparticles with nucleic acids: development of bioresponsive devices, carriers and sensors. Castillo RR, Baeza A, Vallet-Regí M. Biomater Sci 5 353-377 (2017)
  6. Molecular basis for small molecule inhibition of G protein-coupled receptor kinases. Homan KT, Tesmer JJ. ACS Chem Biol 10 246-256 (2015)
  7. The Role of G Protein-coupled Receptor Kinases in Cancer. Yu S, Sun L, Jiao Y, Lee LTO. Int J Biol Sci 14 189-203 (2018)
  8. Applications of Cancer Cell-Specific Aptamers in Targeted Delivery of Anticancer Therapeutic Agents. Kim M, Kim DM, Kim KS, Jung W, Kim DE. Molecules 23 E830 (2018)
  9. Endogenous Control Mechanisms of FAK and PYK2 and Their Relevance to Cancer Development. Naser R, Aldehaiman A, Díaz-Galicia E, Arold ST. Cancers (Basel) 10 E196 (2018)
  10. "Freeze, Don't Move": How to Arrest a Suspect in Heart Failure - A Review on Available GRK2 Inhibitors. Sorriento D, Ciccarelli M, Cipolletta E, Trimarco B, Iaccarino G. Front Cardiovasc Med 3 48 (2016)
  11. Cell-specific aptamers and their conjugation with nanomaterials for targeted drug delivery. Liao J, Liu B, Liu J, Zhang J, Chen K, Liu H. Expert Opin Drug Deliv 12 493-506 (2015)
  12. Expected and unexpected features of protein-binding RNA aptamers. Bjerregaard N, Andreasen PA, Dupont DM. Wiley Interdiscip Rev RNA 7 744-757 (2016)
  13. G protein-coupled receptor signaling: transducers and effectors. Jiang H, Galtes D, Wang J, Rockman HA. Am J Physiol Cell Physiol 323 C731-C748 (2022)
  14. Aptamers as Valuable Molecular Tools in Neurosciences. Wolter O, Mayer G. J Neurosci 37 2517-2523 (2017)
  15. The GRKs Reactome: Role in Cell Biology and Pathology. Chaudhary PK, Kim S. Int J Mol Sci 22 3375 (2021)
  16. The role of HTS in drug discovery at the University of Michigan. Larsen MJ, Larsen SD, Fribley A, Grembecka J, Homan K, Mapp A, Haak A, Nikolovska-Coleska Z, Stuckey JA, Sun D, Sherman DH. Comb Chem High Throughput Screen 17 210-230 (2014)
  17. Structural Insights into Protein-Aptamer Recognitions Emerged from Experimental and Computational Studies. Troisi R, Balasco N, Autiero I, Vitagliano L, Sica F. Int J Mol Sci 24 16318 (2023)
  18. Therapeutic Potential of Aptamer-Protein Interactions. Shraim AS, Abdel Majeed BA, Al-Binni MA, Hunaiti A. ACS Pharmacol Transl Sci 5 1211-1227 (2022)

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