Darrell Davis

davis.jpgProfessor and Chair

Office:

Phone: 801.581-7006
Fax: 801.581.7087

Education:

B.S. 1982 Chemistry, University of Puget Sound
Ph.D. 1988, Organic Chemistry, University of Utah


Research Interests

RNA Structural Biology

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 biomedically 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 only interact weakly with macromolecules.  The University of Utah has an outstanding biomolecular NMR facility with 500, and 600 MHz instruments locally, and access to 800 and 900 MHz instruments at the University of Colorado.

Hepatitis C virus (HCV) infection is a major cause of liver cancer in the US and liver disease associated with HCV accounts for the majority of liver transplants.  In the developing world, a high percentage of HIV patients are also co-infected with HCV, presenting a particularly challenging health problem.  The 5’ untranslated region  of the HCV RNA genome contains a large structured domain that serves as an IRES (internal ribosme entry site) that enables 5’ cap independent RNA translation.  The IRES of HCV is an attractive therapeutic target since it is crucial for HCV replication.  The RNA has a well-defined structure, raising the possibility for developing targeted therapeutics against HCV. 

Our laboratory has solved the structure of a functionally important domain of the HCV IRES RNA in complex with an inhibitor of viral replication.  Current research in the laboratory involves using NMR to screen for additional inhibitors that bind this target.  We are also using NMR for a structure-based drug design initiative aimed at developing next-generation inhibitors with improved potency.  The structure based design project is multi-disciplinary, with a computational chemistry component in collaboration with the Cheatham laboratory, and a synthetic chemistry initiative in collaboration with the Rainier laboratory. 
RDC Figure
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.


Related Links

Davis' Laboratory Website

Visit Davis' Laboratory website


Publications

Peer-Reviewed Publications and Book Chapters

1.  Griffey, R.H., Davis, D.R., Yamaizumi, Z; Nishimura, S., Bax, A., Hawkins, B., Poulter, C.D. (1985) 15N Labeled E. coli  tRNAfMet, tRNAGlu, tRNATyr, and tRNAPhe: Double Resonance and Two dimensional NMR of N1 Labeled Pseudouridine. J. Biol. Chem. 260, 9734 9741.

2.  Davis, D.R.; Griffey, R.H., Yamaizumi, Z., Nishimura, S., Poulter, C.D. (1986) 15N Labeled tRNA: Identification of Dihydrouridine in E. coli  tRNAfMet, tRNALys, and tRNAPhe by 1H 15N Two dimensional NMR. J. Biol. Chem. 261, 3584 3587.

3.  Griffey, R.H., Davis, D.R., Yamaizumi, Z., Nishimura, S., Hawkins, B.L., Poulter, C.D. (1986) 15N Labeled tRNA: Identification of 4 Thiouridine in  E. coli  tRNASer and tRNATyr by 1H 15N Two dimensional NMR.  J. Biol. Chem. 261, 12074 12078.

4.  Davisson, V.J., Davis, D.R., Dixit, V.M., Poulter, C.D. (1987) Synthesis of Nucleotide 5'-Diphosphates from 5' O Tosyl Nucleosides. J. Org. Chem. 52, 1794 1801.

5.  Phillipson, D.W., Edmonds, C.G., Crain, P.F., Smith, D.L., Davis, D.R., McCloskey, J.A. (1987) Isolation and Structure Elucidation of an Epoxide Derivative of the Hypermodified Nucleoside Queosine from  E. coli Transfer RNA. J. Biol. Chem. 262, 3462 3471.

6.  Davis, D.R., Yamaizumi, Z., Nishimura, S., Poulter, C.D. (1989) 15N Labeled 5S RNA. Identification of Uridine Base Pairs in Escherichia coli 5S RNA by 1H 15N Multiple Quantum NMR. Biochemistry. 28, 4105 4108.

7.  Poulter, C.D., Muehlbacher, M., Davis, D.R. (1989) Isopentenyldiphosphate Isomerase. Mechanism of Active Site Directed Irreversible Inhibition by 3 (Fluoromethyl) 3 butenyl Diphosphate. J. Am. Chem. Soc. 111, 3740 3742.

8.  Davis, D.R., Poulter, C.D. (1991) 1H 15N NMR studies of E. coli tRNAPhe from hisT Mutants: A Structural Role for Pseudouridine. Biochemistry 30, 4223 4231.

9.  Davis, D.R. (1991) Application of the 2D TOCSY NOESY Experiment to DNA Assignment. J. Magn. Reson. 94, 401 404.

10. Kosa, J.L., Michelsen, J.W., Louis, H.A., Olsen, J.I., Davis, D.R., Beckerle, M.C., Winge, D.R. (1994) Common Metal Ion Coordination in LIM Domain Proteins. Biochemistry 33, 468 477.

11. Michelsen, J., Louis, H.A., Olsen, J.I., Davis, D.R., Winge, D.R., Beckerle, M.C. (1994) Mutational Analysis of the Metal Sites in a LIM Domain Protein. J. Biol. Chem. 269, 11108 11113.

12. Mohan, V., Griffey, R.H., Davis, D.R. (1995) Structure and Dynamics of MMI Linked Nucleotides. Tetrahedron  51, 6855-6868.

13. Kumar, R.K., Davis, D.R. (1995) Solid-Phase Synthesis of Oligoribonucleotides Containing 2-Thiouridine: Incorporation of 2-Thiouridine Phosphoramidite Without Base Protection. J. Org. Chem. 60, 7726-7727.


14. Davis, D.R. (1995) Stabilization of RNA Stacking by Pseudouridine. Nucleic Acids Res. 23, 5020-5026.

15. Dalluge, J.J., Hashizume, T., Sopchik, A.E., McCloskey, J.A., Davis, D.R. (1996) Conformational Flexibility in RNA: The Role of Dihydrouridine. Nucleic Acids Res. 24, 1073-1079.

16. Davis, D.R., Stillman, D.J. (1997). Altered Structure of the DNA Duplex Recognized by Yeast Transcription Factor Reb1p. Nucleic Acids Res, 25, 668- 675


17. Kumar, R.K., Davis, D.R. (1997) Synthesis and Studies on the Effect of 2-Thiouridine and 4-Thiouridine on Sugar Conformation and RNA Duplex Stability. Nucleic Acids Res.  25, 1272-1280.

18. Kumar, R.K., Davis, D.R. (1997) Structural Studies of 2-Thiouridine in RNA.  Nucleosides Nucleotides, 16, 1469-1472.

19. Durant, P.C., Davis, D.R. (1997) The Effect of Pseudouridine and pH on the Structure And Dynamics of the Anticodon Stem-Loop of tRNALys,3. Nucleic Acids Symposium Series, 36, 56-57.

20.    Mitchell, S.S., Shon, K.J., Foster, M.P., Davis, D.R., Olivera, B.M., Ireland, C.M. (1998) Three-Dimensional Solution Structure of Conotoxin ¿-PIIIE, an Acetylcholine Gated Ion Channel Antagonist. Biochemistry, 37, 1215-1220.

21. Davis, D.R. (1998) Biophysical and Conformational Properties of Modified Nucleosides in RNA. pp. 85-102 In, Modification and Editing of RNA: The Alteration of RNA Structure and Function. (Henri Grosjean & Rob Benne, eds.), ASM Press.

22.  Von Schwedler, U., Stemmler, T.L.,Klishko, V.Y.,  Li, S., Albertine, K.H., Davis,D.R., Sundquist, W.I.. (1998) Proteolytic Refolding of the HIV-1 Capsid Protein Amino Terminus Facilitates Viral Core Assembly. EMBO J. 17, 1555-1568.

23. Davis, D.R, Veltri, C.A., Nielsen, L. (1998) An RNA Model System for Investigation of Pseudouridine Stabilization of the Codon-Anticodon interaction in tRNALys, tRNAHis and tRNATyr. J. Biomol. Struct. Dyn. 15, 1121-1132.

24. Durant, P.C., Davis, D.R. (1999) Stabilization of the Anticodon Stem-Loop of tRNALys,3 by an A+-C Base Pair and by Pseudouridine.   J. Mol. Biol. 285, 115-131

25.    Davis, D.R., Durant, P.C. (1999) Nucleoside Modifications Affect the Structure and Stability of the Anticodon of tRNALys,3. Nucleosides and Nucleotides, 18, 1579-1581.

26. Sundaram, M., Durant, P.C., Davis, D.R. (1999) The Hypermodified Nucleoside mnm5s2U Stabilizes the U-turn in tRNALys. Nucleic Acids Symposium Series, 41, 147-149.

27. Holland, J.A., Hou, Y.-M., Davis, D.R. (1999) NMR structural studies of the tRNACys  amino acceptor stem of Mycoplasma pneumonia. Nucleic Acids Symposium Series, 41, 101-103.

28. Durant, P.C., Davis, D.R. (1999) A tale of two anticodon loops: Extent of modification correlates with anticodon G-C content rather than dynamics. Nucleic Acids Symposium Series, 41, 82-84.

29. Nair, T.M., Myszka, D.G., Davis, D.R. (2000) Surface plasmon resonance kinetic studies of the HIV TAR RNA kissing hairpin complex and its stabilization by 2-thiouridine modification. Nucleic Acids Res. 28, 1935-1940.

30. Sundaram, M., Crain, P.F., Davis, D.R. (2000) Synthesis and Characterization of the Native Anticodon Domain of E. coli tRNALys: Simultaneous Incorporation of Modified Nucleosides mnm5s2U, t6A, and Pseudouridine using Phosphoramidite Chemistry. J. Org. Chem. 65, 5609-5614.

31. Hou, Y.-M., Sundaram, M., Zhang, X., Holland, J.A., Davis, D.R. (2000) Recognition of Functional Groups in an RNA Helix by a Class I tRNA Synthetase. RNA 6, 922-927.

32. Sundaram, M., Durant, P.C., Davis, D.R. (2000) Hypermodified Nucleosides in the Anticodon of tRNALys Stabilize a Canonical U-turn Structure. Biochemistry  39, 12575-12584.


33. Bajji, A. C., Davis, D.R. (2000). Synthesis and Biophysical Characterization of tRNALys,3 Anticodon Stem-Loop RNAs Containing the mcm5s2U Nucleoside. Org. Lett.  2, 3865-3868

34. Hou, Y.-M, Zhang, X., Holland, J.A., Davis, D.R. (2001) An Important 2¿-OH Group for an RNA-Protein Interaction. Nucleic Acids Res. 29, 976-985.

35. Grahn, E., Moss, T., Helgstrand, C., Fridborg, K., Sundaram, M., Tars, K., Lago, H., Stonehouse, N.J., Davis, D.R., Stockley, P.G., Liljas, L. (2001) Structural basis of pyrimidine specificity in the MS2 RNA hairpin-coat protein complex. RNA  7, 1616-1627.

36. Jiang, Y., Blanga, S., Amitsur, M., Meidler, R., Krivosheyev, E., Sundaram, M., Bajji, A.C.,Davis, D.R., Kaufmann, G. (2002) Structural features of tRNALys favored by anticodon nuclease as inferred from reactivities of anticodon stem and loop substrate analogs. J. Biol. Chem. 277, 3836-3841.

37. Pornillos, O.W., Alam, S.L., Rich, R.L., Myszka, D.G., Davis, D.R., Sundquist, W.I. (2002) Structure and functional interactions of the Tsg101 UEV domain. EMBO J. 21, 2397-2406.

38. Bajji, A.C., Davis, D.R. (2002) Synthesis of the tRNALys,3 Anticodon Stem-Loop Domain Containing the Hypermodified ms2t6A Nucleoside. J. Org. Chem. 67, 5352-5358.

39. Pornillos, O., Alam, S.L., Davis, D.R., Sundquist, W.I. (2002) Structure of the Tsg101 UEV domain in complex with the PTAP motif of the HIV-1 p6 protein. Nature. Struct. Biol. 9, 812-817.

40. Bajji, A.C., Sundaram, M., Myszka, D.G., Davis, D.R. (2002). An RNA complex of the HIV-1 A-loop and tRNALys,3 is stabilized by nucleoside modifications. J. Am. Chem. Soc. 124, 14302-14303.



41. Wang, B., Alam, S.L., Payne, M., Meyer, H.H., Payne, M., Stemmler, T.L., Warren, G., Davis, D.R., Sundquist, W.I. (2003). Structure and Ubiquitin Interactions of the Conserved NZF Domain of Npl4.  J. Biol. Chem., 278, 20225-20234.

42. Alam, S.L, Sun, J., Payne, M., Welch, B.D., Blake, B.K., Davis, D.R., Meyer, H.H., Emr, S.D., Sundquist, W.I. (2004) Ubiquitin interactions of NZF zinc fingers.  EMBO J. 23, 1411-1421.

43. Wagner, T.M., Nair, V., Guymon, R., Pomerantz, S.C., Crain, P.F., Davis, D.R., McCloskey, J.A. (2004) A novel method for sequence placement of modified nucleotides in mixtures of transfer RNA. Nucleic Acids Symp Series 48, 263-264

44. Davis, D.R. and Bajji, A.C. (2005) Introduction of hyper-modified nucleotides in RNA. Methods Mol. Biol. 288, 187-204

45. Durant, P.C., Bajji, A.C.. Sundaram, M, Kumar, R.K., Davis, D.R. (2005) Structural effects of hypermodified nucleosides in the E. coli and human tRNALys anticodon loop: The effect of nucleosides s2U, mcm5U, mcm5s2U, mnm5s2U, t6A, and ms2t6A.. Biochemistry 44, 8078-8089.

46. Klaiman, D., Amitsur, M., Blanga-Kanfi, S., Chai, M., Davis, D.R., Kaufmann, G. (2007) Parallel dimerization of PrrC-anticodon nuclease region implicated in tRNALys recognition. Nucleic Acids Res. 35, 4704-14

47. Walewska, A., Skalicky, J. Davis, D.R., Zhang, M.M., Lopez-Vera, E., Watkins, M.,  Han, T., Yoshikami, D.,Olivera, B., Bulaj, G. (2008) NMR-Based Mapping of Disulfide Bridges in Cysteine-Rich Peptides: Application to the |*mu*|-Conotoxin SxIIIA. J. Am. Chem. Soc. 130, 14280-14286.

48. Davis, D.R. (2010) Nucleoside Analogs In Comprehensive Natural Products II Chemistry and Biology; Mander, L., Lui, H.-W. Eds.; Elsevier: Oxford; volume 6, pp.663-682.

49. Paulsen, RB., Seth, P.P., Swayze, E.E., Griffey, R.H., Skalicky, J.J. Cheatham, T.E., Davis, D.R. (2010) Inhibitor Induced Structural Change in the HCV IRES Domain IIa RNA. Proc. Natl. Acad. Sci, USA. 107, 7263-7268. http://www.pnas.org/content/107/16/7263.full

50. Liu, S., Nelson, C., Xiao, L., Lu, L., Seth, P.P., Davis D.R., Hagedorn, C.H. (2010) Measuring Antiviral Activity of Benzimidazole Molecules that Alter IRES RNA Structure with an Infectious Hepatitis C Virus Chimera Expressing Renilla Luciferase. Antiviral Res., in press

51. Davis, D.R., Seth, P.P. (2010) Therapeutic Targeting of the Hepatitis C Virus IRES RNA. Antivir. Chem. Chemotherapy, in press.

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