The VICC.ORG Directory of Doctors, Healthcare Providers & Researchers
Martin Egli, Ph.D.
Professor of Biochemistry
VICC Member
Researcher
Contact Information:
Vanderbilt University Medical Center
868A Robinson Research Building
Nashville, TN 37232-0146
615-343-8070
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.
Publications
- Wang, F, Li, F, Ganguly, M, Marky, LA, Gold, B, Egli, M, Stone, MP A bridging water anchors the tethered 5-(3-aminopropyl)-2''-deoxyuridine amine in the DNA major groove proximate to the N+2 C.G base pair: implications for formation of interstrand 5''-GNC-3'' cross-links by nitrogen mustards. Biochemistry, 47(27), 7147-57, 2008.
- Pallan, PS, Ittig, D, Héroux, A, Wawrzak, Z, Leumann, CJ, Egli, M Crystal structure of tricyclo-DNA: an unusual compensatory change of two adjacent backbone torsion angles. Chem Commun (Camb), (7), 883-5, 2008.
- Wang, Y, Musser, SK, Saleh, S, Marnett, LJ, Egli, M, Stone, MP Insertion of dNTPs opposite the 1,N2-propanodeoxyguanosine adduct by Sulfolobus solfataricus P2 DNA polymerase IV. Biochemistry, 47(28), 7322-34, 2008.
- Pattanayek, R, Williams, DR, Pattanayek, S, Mori, T, Johnson, CH, Stewart, PL, Egli, M Structural model of the circadian clock KaiB-KaiC complex and mechanism for modulation of KaiC phosphorylation. EMBO J, 27(12), 1767-78, 2008.
- Luka, Z, Pakhomova, S, Loukachevitch, LV, Egli, M, Newcomer, ME, Wagner, C 5-methyltetrahydrofolate is bound in intersubunit areas of rat liver folate-binding protein glycine N-methyltransferase. J Biol Chem, 282(6), 4069-75, 2007.
- Pallan, PS, Lubini, P, Egli, M A left-handed supramolecular assembly around a right-handed screw axis in the crystal structure of homo-DNA. Chem Commun (Camb), (14), 1447-9, 2007.
- Pallan, PS, Lubini, P, Bolli, M, Egli, M Backbone-base inclination as a fundamental determinant of nucleic acid self- and cross-pairing. Nucleic Acids Res, 35(19), 6611-24, 2007.
- Li, F, Pallan, PS, Maier, MA, Rajeev, KG, Mathieu, SL, Kreutz, C, Fan, Y, Sanghvi, J, Micura, R, Rozners, E, Manoharan, M, Egli, M Crystal structure, stability and in vitro RNAi activity of oligoribonucleotides containing the ribo-difluorotoluyl nucleotide: insights into substrate requirements by the human RISC Ago2 enzyme. Nucleic Acids Res, 35(19), 6424-38, 2007.
- Loukachevitch, LV, Egli, M Crystallization and preliminary X-ray analysis of Escherichia coli RNase HI-dsRNA complexes. Acta Crystallograph Sect F Struct Biol Cryst Commun, 63(Pt 2), 84-8, 2007.
- Mori, T, Williams, DR, Byrne, MO, Qin, X, Egli, M, McHaourab, HS, Stewart, PL, Johnson, CH Elucidating the Ticking of an In Vitro Circadian Clockwork. PLoS Biol, 5(4), e93, 2007.
- Eoff, RL, Irimia, A, Angel, KC, Egli, M, Guengerich, FP Hydrogen bonding of 7,8-dihydro-8-oxodeoxyguanosine with a charged residue in the little finger domain determines miscoding events in Sulfolobus solfataricus DNA polymerase Dpo4. J Biol Chem, 282(27), 19831-43, 2007.
- Egli, M, Pallan, PS Insights from Crystallographic Studies into the Structural and Pairing Properties of Nucleic Acid Analogs and Chemically Modified DNA and RNA Oligonucleotides. Annu Rev Biophys Biomol Struct, 2007.
- Egli, M, Sarkhel, S Lone pair-aromatic interactions: to stabilize or not to stabilize. Acc Chem Res, 40(3), 197-205, 2007.
- Eoff, RL, Angel, KC, Egli, M, Guengerich, FP Molecular basis of selectivity of nucleoside triphosphate incorporation opposite O6-benzylguanine by sulfolobus solfataricus DNA polymerase DPO4 steady-state and pre-steady-state kinetics and X-ray crystallography of correct and incorrect pairing. J Biol Chem, 2007.
- Pallan, PS, Egli, M Selenium modification of nucleic acids: preparation of oligonucleotides with incorporated 2''-SeMe-uridine for crystallographic phasing of nucleic acid structures. Nat Protoc, 2(3), 647-51, 2007.
- Pallan, PS, Egli, M Selenium modification of nucleic acids: preparation of phosphoroselenoate derivatives for crystallographic phasing of nucleic acid structures. Nat Protoc, 2(3), 640-6, 2007.
- Irimia, A, Eoff, RL, Pallan, PS, Guengerich, FP, Egli, M Structure and activity of Y-class DNA polymerase DPO4 from Sulfolobus solfataricus with templates containing the hydrophobic thymine analog 2,4-difluorotoluene. J Biol Chem, 282(50), 36421-33, 2007.
- Eoff, RL, Irimia, A, Egli, M, Guengerich, FP Sulfolobus solfataricus DNA polymerase Dpo4 is partially inhibited by "wobble" pairing between O6-methylguanine and cytosine, but accurate bypass is preferred. J Biol Chem, 282(2), 1456-67, 2007.
- Egli, M, Lubini, P, Pallan, PS The long and winding road to the structure of homo-DNA. Chem Soc Rev, 36(1), 31-45, 2007.
- Li, F, Sarkhel, S, Wilds, CJ, Wawrzak, Z, Prakash, TP, Manoharan, M, Egli, M 2''-Fluoroarabino- and arabinonucleic acid show different conformations, resulting in deviating RNA affinities and processing of their heteroduplexes with RNA by RNase H. Biochemistry, 45(13), 4141-52, 2006.
- Pattanayek, R, Williams, DR, Pattanayek, S, Xu, Y, Mori, T, Johnson, CH, Stewart, PL, Egli, M Analysis of KaiA-KaiC protein interactions in the cyano-bacterial circadian clock using hybrid structural methods. EMBO J, 25(9), 2017-28, 2006.
- Irimia, A, Zang, H, Loukachevitch, LV, Eoff, RL, Guengerich, FP, Egli, M Calcium is a cofactor of polymerization but inhibits pyrophosphorolysis by the Sulfolobus solfataricus DNA polymerase Dpo4. Biochemistry, 45(19), 5949-56, 2006.
- Egli, M, Pallan, PS, Pattanayek, R, Wilds, CJ, Lubini, P, Minasov, G, Dobler, M, Leumann, CJ, Eschenmoser, A Crystal structure of homo-DNA and nature''s choice of pentose over hexose in the genetic system. J Am Chem Soc, 128(33), 10847-56, 2006.
- Zang, H, Irimia, A, Choi, JY, Angel, KC, Loukachevitch, LV, Egli, M, Guengerich, FP Efficient and high fidelity incorporation of dCTP opposite 7,8-dihydro-8-oxodeoxyguanosine by Sulfolobus solfataricus DNA polymerase Dpo4. J Biol Chem, 281(4), 2358-72, 2006.
- Xia, J, Noronha, A, Toudjarska, I, Li, F, Akinc, A, Braich, R, Frank-Kamenetsky, M, Rajeev, KG, Egli, M, Manoharan, M Gene silencing activity of siRNAs with a ribo-difluorotoluyl nucleotide. ACS Chem Biol, 1(3), 176-83, 2006.
- Pallan, PS, von Matt, P, Wilds, CJ, Altmann, KH, Egli, M RNA-Binding affinities and crystal structure of oligonucleotides containing five-atom amide-based backbone structures. Biochemistry, 45(26), 8048-57, 2006.
- Pallan, PS, Marshall, WS, Harp, J, Jewett, FC, Wawrzak, Z, Brown, BA, Rich, A, Egli, M Crystal structure of a luteoviral RNA pseudoknot and model for a minimal ribosomal frameshifting motif. Biochemistry, 44(34), 11315-22, 2005.
- Zang, H, Goodenough, AK, Choi, JY, Irimia, A, Loukachevitch, LV, Kozekov, ID, Angel, KC, Rizzo, CJ, Egli, M, Guengerich, FP DNA adduct bypass polymerization by Sulfolobus solfataricus DNA polymerase Dpo4: analysis and crystal structures of multiple base pair substitution and frameshift products with the adduct 1,N2-ethenoguanine. J Biol Chem, 280(33), 29750-64, 2005.
- Egli, M, Minasov, G, Tereshko, V, Pallan, PS, Teplova, M, Inamati, GB, Lesnik, EA, Owens, SR, Ross, BS, Prakash, TP, Manoharan, M Probing the influence of stereoelectronic effects on the biophysical properties of oligonucleotides: comprehensive analysis of the RNA affinity, nuclease resistance, and crystal structure of ten 2''-O-ribonucleic acid modifications. Biochemistry, 44(25), 9045-57, 2005.
- Diop-Frimpong, B, Prakash, TP, Rajeev, KG, Manoharan, M, Egli, M Stabilizing contributions of sulfur-modified nucleotides: crystal structure of a DNA duplex with 2''-O-[2-(methoxy)ethyl]-2-thiothymidines. Nucleic Acids Res, 33(16), 5297-307, 2005.
- Haeberli, P, Berger, I, Pallan, PS, Egli, M Syntheses of 4''-thioribonucleosides and thermodynamic stability and crystal structure of RNA oligomers with incorporated 4''-thiocytosine. Nucleic Acids Res, 33(13), 3965-75, 2005.
- Egli, M Deoxyribo nanonucleic acid"; antiparallel, parallel, and unparalleled. Chem Biol, 11(8), 1027-9, 2004.
- Prakash, TP, Püschl, A, Lesnik, E, Mohan, V, Tereshko, V, Egli, M, Manoharan, M 2''-O-[2-(guanidinium)ethyl]-modified oligonucleotides: stabilizing effect on duplex and triplex structures. Org Lett, 6(12), 1971-4, 2004.
- Xu, Y, Mori, T, Pattanayek, R, Pattanayek, S, Egli, M, Johnson, CH Identification of key phosphorylation sites in the circadian clock protein KaiC by crystallographic and mutagenetic analyses. Proc Natl Acad Sci U S A, 101(38), 13933-8, 2004.
- Egli, M Nucleic acid crystallography: current progress. Curr Opin Chem Biol, 8(6), 580-91, 2004.
- Cook, S, Hugli, O, Egli, M, Ménard, B, Thalmann, S, Sartori, C, Perrin, C, Nicod, P, Thorens, B, Vollenweider, P, Scherrer, U, Burcelin, R Partial gene deletion of endothelial nitric oxide synthase predisposes to exaggerated high-fat diet-induced insulin resistance and arterial hypertension. Diabetes, 53(8), 2067-72, 2004.
- Pattanayek, R, Sethaphong, L, Pan, C, Prhavc, M, Prakash, TP, Manoharan, M, Egli, M Structural rationalization of a large difference in RNA affinity despite a small difference in chemistry between two 2''-O-modified nucleic acid analogues. J Am Chem Soc, 126(46), 15006-7, 2004.
- Johnson, CH, Egli, M Visualizing a biological clockwork''s cogs. Nat Struct Mol Biol, 11(7), 584-5, 2004.
- Pattanayek, R, Wang, J, Mori, T, Xu, Y, Johnson, CH, Egli, M Visualizing a circadian clock protein: crystal structure of KaiC and functional insights. Mol Cell, 15(3), 375-88, 2004.
- Egli, M, Tereshko, V, Mushudov, GN, Sanishvili, R, Liu, X, Lewis, FD Face-to-face and edge-to-face pi-pi interactions in a synthetic DNA hairpin with a stilbenediether linker. J Am Chem Soc, 125(36), 10842-9, 2003.
- Sarkhel, S, Rich, A, Egli, M Water-nucleobase "stacking": H-pi and lone pair-pi interactions in the atomic resolution crystal structure of an RNA pseudoknot. J Am Chem Soc, 125(30), 8998-9, 2003.
- Pallan, PS, Wilds, CJ, Wawrzak, Z, Krishnamurthy, R, Eschenmoser, A, Egli, M Why does TNA cross-pair more strongly with RNA than with DNA? an answer from X-ray analysis. Angew Chem Int Ed Engl, 42(47), 5893-5, 2003.
- Teplova, M, Wilds, CJ, Wawrzak, Z, Tereshko, V, Du, Q, Carrasco, N, Huang, Z, Egli, M Covalent incorporation of selenium into oligonucleotides for X-ray crystal structure determination via MAD: proof of principle. Multiwavelength anomalous dispersion. Biochimie, 84(9), 849-58, 2002.
- Wilds, CJ, Wawrzak, Z, Krishnamurthy, R, Eschenmoser, A, Egli, M Crystal structure of a B-form DNA duplex containing (L)-alpha-threofuranosyl (3''-->2'') nucleosides: a four-carbon sugar is easily accommodated into the backbone of DNA. J Am Chem Soc, 124(46), 13716-21, 2002.
- Egli, M DNA-cation interactions: quo vadis. Chem Biol, 9(3), 277-86, 2002.
- Wilds, CJ, Maier, MA, Tereshko, V, Manoharan, M, Egli, M Direct observation of a cytosine analogue that forms five hydrogen bonds to guanosine: guanidino G-clamp. Angew Chem Int Ed Engl, 41(1), 115-7, 2002.
- Joseph, B, Egli, M, Koppekin, A, Thompson, T Food choice in people with Prader-Willi syndrome: quantity and relative preference. Am J Ment Retard, 107(2), 128-35, 2002.
- Egli, M, Minasov, G, Su, L, Rich, A Metal ions and flexibility in a viral RNA pseudoknot at atomic resolution. Proc Natl Acad Sci U S A, 99(7), 4302-7, 2002.
- Wilds, CJ, Pattanayek, R, Pan, C, Wawrzak, Z, Egli, M Selenium-assisted nucleic acid crystallography: use of phosphoroselenoates for MAD phasing of a DNA structure. J Am Chem Soc, 124(50), 14910-6, 2002.
- Tereshko, V, Teplova, M, Brunzelle, J, Watterson, DM, Egli, M Crystal structures of the catalytic domain of human protein kinase associated with apoptosis and tumor suppression. Nat Struct Biol, 8(10), 899-907, 2001.
- Tereshko, V, Wilds, CJ, Minasov, G, Prakash, TP, Maier, MA, Howard, A, Wawrzak, Z, Manoharan, M, Egli, M Detection of alkali metal ions in DNA crystals using state-of-the-art X-ray diffraction experiments. Nucleic Acids Res, 29(5), 1208-15, 2001.
- Joseph, B, Egli, M, Sutcliffe, JS, Thompson, T Possible dosage effect of maternally expressed genes on visual recognition memory in Prader-Willi syndrome. Am J Med Genet, 105(1), 71-5, 2001.
- Wilds, CJ, Minasov, G, Natt, F, von Matt, P, Altmann, KH, Egli, M Studies of a chemically modified oligodeoxynucleotide containing a 5-atom amide backbone which exhibits improved binding to RNA. Nucleosides Nucleotides Nucleic Acids, 20(4-7), 991-4, 2001.
- Tereshko, V, Wallace, ST, Usman, N, Wincott, FE, Egli, M X-ray crystallographic observation of "in-line" and "adjacent" conformations in a bulged self-cleaving RNA/DNA hybrid. RNA, 7(3), 405-20, 2001.
- Sachdev, RN, Egli, M, Stonecypher, M, Wiley, RG, Ebner, FF Enhancement of cortical plasticity by behavioral training in acetylcholine-depleted adult rats. J Neurophysiol, 84(4), 1971-81, 2000.
- Teplova, M, Tereshko, V, Sanishvili, R, Joachimiak, A, Bushueva, T, Anderson, WF, Egli, M The structure of the yrdC gene product from Escherichia coli reveals a new fold and suggests a role in RNA binding. Protein Sci, 9(12), 2557-66, 2000.
- Egli, M, Roper, T, Feurer, I, Thompson, T Architectural acoustics in residences for adults with mental retardation and its relation to perceived homelikeness. Am J Ment Retard, 104(1), 53-66, 1999.
- Egli, M, Joseph, B, Thompson, T Transfer of social attributions in stimulus equivalence classes by preschool children. Psychol Rep, 80(1), 3-21, 1997.
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