Poster abstracts
Poster number 3 submitted by Daniel V. Cantu
Preliminary analysis of K-Ras structural dynamics via NMR
Daniel Cantu (Biophysics Graduate Program), Yina Gu (Department of Chemistry and Biochemistry), Lei Bruschweiler-Li (Department of Chemistry and Biochemistry, Campus Chemical Instrument Center), Alex L. Hansen (Department of Chemistry and Biochemistry, Campus Chemical Instrument Center)
Abstract:
Oncogenic GTPase K-Ras has been considered an “undruggable” protein for over 30 years due to a relatively smooth and static structure, according X-Ray crystal structures. However, preliminary NMR data and MD simulation data collected in our lab suggest two important loop regions, named Switch I and Switch II, are highly dynamic and may adopt multiple confirmations. Switch I and Switch II are responsible for numerous protein-protein interactions, binding of guanosine nucleotides, and the hydrolysis of GTP to GDP. We believe these loops regions allow K-Ras to adopt an ensemble of excited-state confirmations that X-ray crystallography could not detect. NMR has the ability to detect protein dynamics in sparsely populated excited states. Therefore, we plan to use NMR to measure structural dynamics experiments, including CMPG and CEST, that report on the μs - ms timescale. We will perform these experiments on wild-type K-Ras and oncogenic G12D K-Ras, a predominant oncogenic mutation found in about 36% of all K-Ras mutations. By combining NMR data MD simulations with various crystal structures from PDB, we will attempt to comprehensively identify possible binding sites or other structural elements with the potential for binding therapeutic drugs for oncogenic K-Ras. Our poster will describe preliminary NMR data.
Keywords: NMR, K-Ras, Protein Dynamics