Distinguished Professor of Chemistry and Biochemistry

Office: Tata Hall 1200B
Phone: 858-534-3058
Email: ekomives@ucsd.edu
Web: komiveslab.ucsd.edu
Group: View group members

2000

Kaiser Award for Excellence in Teaching

2000

Barany Award for Contributions to Biophysics

1992-1995

Searle Scholar

1991-1996

Rita Allen Scholar

1987-1990

N.I.H. Postdoctoral Fellow, Harvard University

The long-term goal of research in the Komives lab is to understand the parameters that govern protein-protein recognition and the mechanisms by which these interactions contribute to biological function. The relative importance of factors such as hydrophobic effects, electrostatic interactions and dynamics are being defined for several different interactions. These parameters are explored by a combination of molecular biological techniques, protein chemistry, surface plasmon resonance, multidimensional NMR, and mass spectrometry. One project aims to discover how thrombomodulin (TM) converts the pro-coagulant activity of thrombin to anti-coagulant activity. The thrombin-TM interaction involves diffusion-controlled association that is highly electrostatically steered. The binding has no favorable enthalpy change, but is instead driven by entropy. In collaboration with the McCammon group, we have obtained evidence from Accelerated Molecular Dynamics that the TM binding site is dynamically coupled to motions at the thrombin active site. We recently were able to obtain beautiful NMR spectra for thrombin, and are now characterizing its dynamics.

A second project in the lab is a joint effort with the G. Ghosh, A. Hoffmann, P. Wolynes and J. Dyson labs. This involves understanding the signal transduction mediated by the family of NFkB transcription factors and their IkB inhibitors. We determined that the binding energy of the complex between IkBa and NFkB (p50/p65) lies at the ends of the binding interface. We showed that IkBa folds upon binding to NFkB and that the fifth and sixth ankyrin repeats are weakly folded according to amide exchange experiments. The weakly-folded parts of IkBa appear to be important for facilitating removal of NFkB from transcription sites and we showed by single molecule FRET that they slowly fluctuate between folded and unfolded states. Taking off on this project, we are now investigating other protein-protein interactions mediated by ankyrin-repeat domain proteins. In particular, we are studying the interaction between ASB9, one member of a large family of E3 ubiquitin ligases, and its target, Creatine Kinase.

A third project in the lab is to develop novel proteases for proteomics applications. Starting from alphalytic protease, a particularly stable and highly active protease, we are evolving a family of proteases with unique substrate specificity to expand the protein sequence coverage in proteomics experiments.

Biophysics
Macromolecular Structure

Ensemble of thrombin structures that best represents the NMR-derived residual dipolar couplings

Single molecule FRET traces showing the fluctuations within the IkBa molecule