Martin Egli, Ph.D.
Professor of Biochemistry
- : email@example.com
- : 615-343-8070
868A Robinson Research Building
23rd & Pierce Avenue
Nashville, - 37232-0146
Structural biology of circadian clocks, nucleic acids & DNA polymerases
Name: Egli, Martin
Title: Professor of Biochemistry
Office Address: 868A RRB
Phone Number: (615) 343-8070
Lab URL: http://structbio.vanderbilt.edu/~eglim/
Research Keywords: Macromolecular X-ray Crystallography
Research Specialty: Structural Biology of Circadian Clocks, native and chemically modified nucleic acids, and trans-lesion DNA polymerase-DNA adduct interactions
Research Description: On-going efforts in my laboratory focus on the following areas.
(i) Structure/function analyses of native and chemically modified nucleic acids and etiology of nucleic acid structure. Using chemical synthesis and structure determination at high resolution, the effects of chemical modifications on the structures of DNA and RNA are examined and the results correlated with stability and in vitro and in vivo activity data to direct the design of nucleic acid analogs with improved efficacies for antisense and RNAi applications. We are collaborating with researchers from Alnylam Pharmaceuticals Inc. (Cambridge, MA) and Isis Pharmaceuticals Inc. (Carlsbad, CA) to exploit insights from structural studies for the design of next generation antisense and siRNA therapeutics.
(ii) Chemistry and biology of carcinogen-DNA adducts. This program examines relationships between the structure and biological processing of damaged bases by Y-class trans-lesion DNA polymerases (i.e. Dpo4 from Sulfolobus solfataricus and human Pol-iota, Pol-kappa and Pol-eta). Using in vitro primer extension assays in combination with steady state and pre-steady state kinetics as well as mass spectrometry, we are probing the effects on the accuracy of replication of a range of adducts inside the template strand (8-oxo-dG, O6-methyl-dG, N2-methyl-dG, 1,N2-etheno-dG, acrolein, cyclic pyrimidine dimers and others). Crystal structures of binary Pol-DNA and ternary Pol-DNA-dNTP complexes are determined to shed light on the consequences of individual lesions for the accuracy of bypass.
(iii) The cyanobacterial KaiABC circadian clock. The circadian clock of Synechococcus elongatus can be reconstituted in vitro with the three proteins KaiA, KaiB and KaiC in the presence of ATP and Mg2+. KaiC is the central cog and exhibits kinase, phosphatase and ATPase activities, KaiA enhances KaiC phosphorylation and KaiB antagonizes KaiA. Remarkably, this post-translational timer exhibits all the hallmarks of circadian clocks – a period of ca. 24 hours, entrainment and temperature compensation – thus permitting its dissection by biochemical and biophysical means. Using a hybrid structural approach including single crystal X-ray crystallography, electron microscopy and small angle X-ray and neutron scattering in combination with functional studies in vitro and in vivo, we are analyzing the protein-protein interactions and mechanistic aspects of this molecular clock.