The rockefeller university

Event Details

Type

Friday Lecture Series

Speaker(s)

Kevan Shokat, Ph.D., professor and chair, department of cellular and molecular pharmacology, University of California, San Francisco; investigator, Howard Hughes Medical Institute

Speaker bio(s)

Somatic mutations in the small GTPase K-Ras are the most common activating lesions found in human cancer, and are generally associated with poor response to standard therapies. Efforts to directly target this oncogene have faced difficulties due to its picomolar affinity for GTP/GDP and the absence of known allosteric regulatory sites. Oncogenic mutations result in functional activation of Ras family proteins by impairing GTP hydrolysis. With diminished regulation by GTPase activity, the nucleotide state of Ras becomes more dependent upon relative nucleotide affinity and concentration. This gives GTP an advantage over GDP and increases the proportion of active GTP-bound Ras. Dr. Shokat will discuss the development of small molecules that irreversibly bind to a common oncogenic mutant, K-RasG12C. These compounds rely on the mutant cysteine for binding and therefore do not affect the wild type protein. Crystallographic studies reveal the formation of a new pocket that is not apparent in previous structures of Ras, beneath the effector binding switch-II region. These data provide structure-based validation of a novel allosteric regulatory site on Ras that is targetable in a mutant-specific manner.

Mitochondria have long been implicated in the pathogenesis of Parkinson's disease. Mutations in the mitochondrial kinase PINK1 that reduce kinase activity are associated with mitochondrial defects and result in an autosomal-recessive form of early-onset Parkinson's disease. Therapeutic approaches for enhancing the activity of PINK1 have not been considered because no allosteric regulatory sites for PINK1 are known. Dr. Shokat will discuss an alternative strategy, a neo-substrate approach involving the ATP analog kinetin triphosphate, which can be used to increase the activity of both Parkinson's-related mutant PINK1(G309D) and PINK1(wild type). Discovery of neo-substrates for kinases could provide a heretofore-unappreciated modality for regulating kinase activity.

 

Dr. Shokat recieved his Ph.D. in organic chemistry at the University of California, Berkeley, working with Dr. Peter Schultz, and completed postdoctoral studies in immunology at Stanford University with Dr. Chris Goodnow. Dr. Shokat began his independent research career at Princeton University, where he was promoted from assistant to associate professor in four years. He has received numerous awards, including being named a fellow of several research foundations including the Pew Foundation, Searle Foundation, Sloan Foundation, Glaxo-Wellcome Foundation and the Cotrell Foundation. He has also received the Eli Lilly Award, and has been inducted into the National Academy of Sciences (2010), the Institute of Medicine (2011), and the American Academy of Arts and Sciences (2011). Dr. Shokat has successfully commercialized discoveries from his laboratory, including chemical genetic tools for tracking and validating protein kinase drug targets.

Open to

Public

Reception

Refreshments, 3:15 p.m. - 3:45 p.m., Abby Lounge

Contact

Alena Powell

Phone

(212) 327-7745

Sponsor

Alena Powell
(212) 327-7745
apowell@rockefeller.edu

Readings

http://librarynews.rockefeller.edu/?p=3233