Allosteric modulation of a human protein kinase with monobodies

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 116; no. 28; pp. 13937 - 13942
• Main Authors: Zorba, Adelajda, Nguyen, Vy, Koide, Akiko, Hoemberger, Marc, Zheng, Yuejiao, Kutter, Steffen, Kim, Chansik, Koide, Shohei, Kern, Dorothee
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 09.07.2019
• Subjects: 60 APPLIED LIFE SCIENCES; Adenosine Triphosphate - chemistry; Adenosine Triphosphate - metabolism; allosteric drugs; Allosteric properties; Allosteric Regulation - genetics; allostery; Aurora A; Aurora Kinase A - antagonists & inhibitors; Aurora Kinase A - chemistry; Aurora Kinase A - genetics; Aurora Kinase B - antagonists & inhibitors; Aurora Kinase B - chemistry; Aurora Kinase B - genetics; Binding sites; Binding Sites - genetics; Biological Sciences; Carrier Proteins - chemistry; Carrier Proteins - genetics; Crystal structure; Crystallography, X-Ray; Drug delivery; Drug Design; Drug development; Fibronectin Type III Domain - genetics; Humans; kinase; Kinases; Modulation; Modulators; monobody; Physical Sciences; Protein Conformation; Protein kinase; Protein Kinase Inhibitors - chemistry; Protein Kinases - chemistry; Protein Kinases - genetics; science & technology - other topics; Selectivity; kinase; monobody; Aurora A; allosteric drugs; allostery
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.1906024116

Despite being the subject of intense effort and scrutiny, kinases have proven to be consistently challenging targets in inhibitor drug design. A key obstacle has been promiscuity and consequent adverse effects of drugs targeting the ATP binding site. Here we introduce an approach to controlling kinase activity by using monobodies that bind to the highly specific regulatory allosteric pocket of the oncoprotein Aurora A (AurA) kinase, thereby offering the potential for more specific kinase modulators. Strikingly, we identify a series of highly specific monobodies acting either as strong kinase inhibitors or activators via differential recognition of structural motifs in the allosteric pocket. X-ray crystal structures comparing AurA bound to activating vs inhibiting monobodies reveal the atomistic mechanism underlying allosteric modulation. The results reveal 3 major advantages of targeting allosteric vs orthosteric sites: extreme selectivity, ability to inhibit as well as activate, and avoidance of competing with ATP that is present at high concentrations in the cells. We envision that exploiting allosteric networks for inhibition or activation will provide a general, powerful pathway toward rational drug design.