Darrell R. Davis
Professor and Chair of Medicinal Chemistry and
Adjunct Professor of Biochemistry
B.S. University of Puget Sound
Ph.D. University of Utah
Darrell Davis' Lab Page
Darrell Davis' PubMed Literature Search
Molecular Biology Program
Biological Chemistry Program
My laboratory is involved in the study of nucleic acid and protein structure using high-field NMR spectroscopy. We have recently developed a structure-based drug design program focused on discovering and optimizing small molecules that interact with therapeutically relevant RNA targets. NMR spectroscopy is uniquely suited to solving the 3D structures of RNA domains in complex with inhibitor molecules, and NMR also is a unique tool for identifying lead compounds that interact with a variety of relevant targets The University of Utah has an outstanding biomolecular NMR facility with 500, 600, and 800 MHz instruments locally, and access to 800 and 900 MHz instruments at the University of Colorado.
The 5’ untranslated region of the HCV RNA genome contains a large structured domain that serves as an IRES (internal ribosome entry site) that enables 5’ cap independent RNA translation. The HCV IRES is a functional prototype for protein expression regulation at the translational level. This RNA has a well-defined structure, providing a ready-made model for developing RNA targeted HCV inhibitors. HCV also provides a paradigm for understanding RNA virus replication, and insights obtained from this system are being applied to distinct, emerging viral threats.
We are now applying the structural and biophysical principles learned from HCV to broader principles of translational control in viruses such as Zika virus and Dengue virus. These principles are also being applied to discover RNA targets of small molecules that are involved in translational regulation of cellular genes that may be important in cancer. Projects in the laboratory provide the opportunity for biophysical and structural investigation of conserved translational mechanisms that appear to be of broad biological relevance.
(Left) Superposition of NMR structures for a domain of the hepatitis C virus internal ribosomal entry site RNA complexed with an inhibitor. (Right) Correlation of experimental CH residual dipolar coupling NMR restraints. Open circles are calculated values of the free RNA plotted against the experimental RDC values of the complex, showing that the free RNA does not fit the experimental data, while closed circles are for the inhibited structure indicating a good fit with experiment.
- Galindo-Murillo, R., Davis, D.R., Cheatham, T.E. (2016) Probing the influence of hypermodified residues within the tRNALys,3 anticodon stem loop interacting with the A-loop primer sequence from HIV-1. Biochem. Biophys. Acta. 1860, 607-617.
- Henriksen, N.M., Hayatshahi, H.S., Davis, D.R., Cheatham, T.E. (2014) Structural and energetic analysis of 2-aminobenzimidazole inhibitors in complex with the hepatitis C virus IRES RNA using molecular dynamics simulations. J. Chem. Inf. Model. 54, 1758-1772.
- Henriksen, N.M., Davis, D.R., and Cheatham, T.E (2012) Molecular dynamics re-refinement of two different small RNA loop structures using the original NMR data suggest a common structure. J. Biomol. NMR, 53, 321-339.
- Liu S, Nelson C, Xiao L, Lu L, Seth PP, Davis DR, Hagedorn CH (2011) Measuring Antiviral Activity of Benzimidazole Molecules that Alter IRES RNA Structure with an Infectious Hepatitis C Virus Chimera Expressing Renilla Luciferase. Antiviral Res.89, 54-63.
- Paulsen RB, Seth PP, Swayze EE, Griffey RH, Skalicky JJ, Cheatham TE, Davis DR (2010) Inhibitor Induced Structural Change in the HCV IRES Domain IIa RNA. Proc Natl Acad Sci USA107, 7263-7268.