Vanderbilt University School of Medicine

Egli, Martin , Ph.D.
Professor of Biochemistry

Lab Url: http://structbio.vanderbilt.edu/~eglim/

Phone Number: (615) 343-8070

Email Address:martin.egli@vanderbilt.edu

Egli, Martin's picture

Office Address   Mailing Address

RRB 868

868A RRB 37232


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.

Publications
Pallan, PS, Ittig, D, H??roux, 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.

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. PMCID:2435126

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. PMCID:2730145

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. PMCID:2753402

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.

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.

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.

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.

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.

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. PMCID:2095806

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. PMCID:2330121

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.

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. PMCID:1831719

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.

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, 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. PMCID:2095819

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.

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.

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.

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. PMCID:2553321

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.

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. PMCID:1456936

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.

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.

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. PMCID:1216336

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.

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. PMCID:1178003

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. PMCID:2556298

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.

Cook, S, Hugli, O, Egli, M, Menard, 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.

Egli, M. Nucleic acid crystallography: current progress. Curr Opin Chem Biol, 8(6), 580-91, 2004.

Egli, M. "Deoxyribo nanonucleic acid"; antiparallel, parallel, and unparalleled. Chem Biol, 11(8), 1027-9, 2004.

Johnson, CH, Egli, M. Visualizing a biological clockwork''s cogs. Nat Struct Mol Biol, 11(7), 584-5, 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.

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.

Prakash, TP, P??schl, 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. PMCID:518856

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.

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.

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.

Egli, M. DNA-cation interactions: quo vadis. Chem Biol, 9(3), 277-86, 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. PMCID:123643

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.

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, 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.

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.

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.

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.

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, 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. PMCID:1370097

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. PMCID:29719

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.

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. PMCID:2144518

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.


Postdoctoral Position Available
No

Postdoctoral Position Details
N/A

Updated Date
11/19/2010



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