个人简介

Professor, born 1951; B. S. University of California, Davis (1973); Ph. D. Physical Chemistry, University of California, Berkeley (1979); Operations Manager NIH NMR Facility, Stanford University (1980-1982); Research Assistant Professor, University of Washington (1983-1985).

研究领域

Biophysical Chemistry: Proteins, Nucleic Acids, NMR Spectroscopy — Magnetic resonance methods are being used to investigate the solution structure of proteins and DNA, and the nature and range of their conformational fluctuations, allowing a better understanding of how these molecules carry out their various functions. Research in Professor Wemmer's laboratory is aimed at understanding the interactions which govern the function of various biopolymers (proteins, DNA, RNA). These interactions include those which stabilize particular conformations of the molecule, as well as those through which different molecules interact to form specific complexes, and carry out their functions. The major tool used is nuclear magnetic resonance, particularly multidimensional methods, often with biosynthetic isotope enrichment. For many moderate size biopolymers the resonances can be systematically assigned to particular sites in the molecule. Nuclear Overhauser effect measurements can be used to determine interproton distances, from which structures can be calculated. In addition, structural fluctuations can be detected using measurements of spin relaxation, or exchange of amide or imino protons. These general approaches are being applied to many different problems, a few of which are described below. Solution structures have been determined for a variety of complexes of DNA oligomers with small molecule ligands. The natural product distamycin binds in the minor groove in A·T rich sequences. It has been found that there are two forms of complex, one with a single ligand in a narrow groove, and one with two ligands side-by-side in a wider groove. Examining the sequence dependence of binding allows the modification of a design for G·C recognizing ligands to specifically recognize mixed A·T/G·C sequences for the first time. The ideas are now being extended to linked dimers, and to mixed designs which recognize longer sequences. Such small molecule ligands which recognize DNA sequence specifically may be useful in molecular biology, and perhaps later as pharmaceuticals. Over the past few years most of the group's studies of proteins have focused on those involved in regulation of genetic expression. Several of these proteins are transcription factors, which are modular structures which recognize DNA and assemble other proteins into the transcription complex. While the domains which recognize DNA are well structured, those involved in forming protein-protein complexes seem to be primarily disordered. Work is now focusing on complexes to try to understand how such domains function. Other regulatory proteins under study include a bacterial repressor, and a sequence specific RNA binding protein which regulates splicing. For a majority of these studies we take advantage of isotope enrichment with 15N and 13C with 3D and 4D NMR experiments. Other ongoing studies in the lab examine unusual DNA structures, a variety of cofactors, peptides, and unnatural "bio"polymers. We continue to try to exploit recent advances in 3H labeling and NMR to address biomolecular problems.

Biophysical Chemistry: Proteins, Nucleic Acids, NMR Spectroscopy — Magnetic resonance methods are being used to investigate the solution structure of proteins and DNA, and the nature and range of their conformational fluctuations, allowing a better understanding of how these molecules carry out their various functions. Research in Professor Wemmer's laboratory is aimed at understanding the interactions which govern the function of various biopolymers (proteins, DNA, RNA). These interactions include those which stabilize particular conformations of the molecule, as well as those through which different molecules interact to form specific complexes, and carry out their functions. The major tool used is nuclear magnetic resonance, particularly multidimensional methods, often with biosynthetic isotope enrichment. For many moderate size biopolymers the resonances can be systematically assigned to particular sites in the molecule. Nuclear Overhauser effect measurements can be used to determine interproton distances, from which structures can be calculated. In addition, structural fluctuations can be detected using measurements of spin relaxation, or exchange of amide or imino protons. These general approaches are being applied to many different problems, a few of which are described below. Solution structures have been determined for a variety of complexes of DNA oligomers with small molecule ligands. The natural product distamycin binds in the minor groove in A·T rich sequences. It has been found that there are two forms of complex, one with a single ligand in a narrow groove, and one with two ligands side-by-side in a wider groove. Examining the sequence dependence of binding allows the modification of a design for G·C recognizing ligands to specifically recognize mixed A·T/G·C sequences for the first time. The ideas are now being extended to linked dimers, and to mixed designs which recognize longer sequences. Such small molecule ligands which recognize DNA sequence specifically may be useful in molecular biology, and perhaps later as pharmaceuticals. Over the past few years most of the group's studies of proteins have focused on those involved in regulation of genetic expression. Several of these proteins are transcription factors, which are modular structures which recognize DNA and assemble other proteins into the transcription complex. While the domains which recognize DNA are well structured, those involved in forming protein-protein complexes seem to be primarily disordered. Work is now focusing on complexes to try to understand how such domains function. Other regulatory proteins under study include a bacterial repressor, and a sequence specific RNA binding protein which regulates splicing. For a majority of these studies we take advantage of isotope enrichment with 15N and 13C with 3D and 4D NMR experiments. Other ongoing studies in the lab examine unusual DNA structures, a variety of cofactors, peptides, and unnatural "bio"polymers. We continue to try to exploit recent advances in 3H labeling and NMR to address biomolecular problems.

近期论文

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Michalak, D.J., Xu, S., Lowery, T.J., Crawford, C.W., Ledbetter, M., Wemmer, D.E., Budker, D., Pines, A. “Relaxivity of Gadolinium Complexes Detected by Atomic Magnetometry” Mag Res Med. (2011). Wickliffe, K.E., Lorenz, S., Wemmer, D.E., Kuriyan, J., Rape, M. “The mechanism of linkage-specific ubiquitin chain elongation by a single-subunit E2” Cell 144, 769-81 (2011). Hernandez, J.A., Phillips, A.H., Erbil, K.W., Zhao, D., Zeymer, C., Pelton, J.G., Wemmer, D.E., Rubio, L.M. “Nitrogenase recruits a SAM (Sterile Alpha Motif) interaction domain: cofactor insertion involves metallocluster-binding and SAM-interaction domains” J Biol Chem. 286, 6321-28 (2011). Damo, S.M., Phillips, A.H., Young, A.L., Li, S., Woods, V.L.Jr., Wemmer, D.E. “Probing the Prion Protein Conformation in a Fibril with Hydrogen Exchange” J.Biol.Chem. 285, 32303-11 (2010). Schilling, F., Schröder, L., Palaniappan, K.K., Zapf, S., Wemmer, D.E., Pines, A. “MRI Thermometry Based on Encapsulated Hyperpolarized Xenon” Chem Phys Chem 11, 3529-33 (2010). Wetzler, M., Wemmer, D.E. “Facile Dimer Synthesis for DNA-binding Polyamide Ligands” Org. Lett. 12, 3488-90 (2010). Meldrum, T., Schröder, L., Denger, P., Wemmer, D.E., Pines, A. “Xenon-based Molecular Sensors in Lipid Suspensions” J. Magn. Res. 205, 242-46 (2010). Kim, K.-S., Pelton, J.G., Andersen, U., Kustu, S. and Wemmer, D.E. “The Rut pathway for pyrimidine degradation: Novel chemistry and toxicity problems” J. Bact. 192, 4089-102 (2010). Meldrum, T., Seim, K.L., Bajaj, V.S., Palaniappan, K., Wu, W., Francis, M.B., Wemmer, D.E., Pines, A. “A Xenon-based Molecular Sensor Assembled on an MS2 Viral Capsid Scaffold” J.Am.Chem.Soc. 132, 5936-37 (2010). Sterling, H.J., Batchelor, J.D., Wemmer, D.E. and Williams, E.R. “Electrospray Ionization Mass Spectrometery of a Non-Covalent Protein Complex with Essential Salts via Buffer Loading” J. Am. Soc. Mass. Spec. 21, 1045-49 (2010). Cetinkol, O.P., Dibble, D.C., Cheng, C., Kent, M.S., Knierim, B., Auer, M., Wemmer, D.E., Pelton, J.G., Melnichenko, Y.B., Ralph, J., Simmons, B.A. and Holmes, B.M. “Understanding the Impact of Ionic Liquid Pretreatment on Eucalyptus” Biofuels 1, 33-46 (2010). Erbil, W.K., Price, M.S., Wemmer, D.E. and Marletta, M.A. “A structural basis for H-NOX signaling by trapping a kinase inhibitory conformation of the H-NOX from S.oneidensis” Proc.Natl.Acad.Sci.USA 106, 19753-60 (2009). Inwood, W., Hall, J. Kim, K.-S., Demirkahyan, L., Wemmer, D.E., Zgurskaya, H., Kustu, S. “Epistatic Effects of the Protease/Chaperone HflB on Soe Damaged Froms of the Escherichia coli Ammonium Channel AmtB” Genetics 183, 1327-1340 (2009). Batchelor, J.D., Sterling, H.J., Hong, E., Williams, E.R., Wemmer, D.E. “Receiver domains control the active state stoichiometry of Aquifex aeolicus s54 activator NtrC4, as revealed by electrospray mass spectrometry” J. Mol. Biol. 393, 634-43 (2009). Jura, N., Endres, N.F., Engel, K., Deindl, S., Das, R., Lamers, M.H., Wemmer, D.E., Zhang, X., Kuriyan, J. “Structural coupling between the juxtamembrane segment of the EGF receptor and activation of the catalytic domain” Cell 237, 1293-1307 (2009). Hong, E., Doucleff, M. and Wemmer, D.E. “Structure of the RNA-Polymerase Core Binding Domain of s54 Reveals a Potential Conformational Fracture Point” J. Molec. Biol. 390, 70-82 (2009). Ledbetter, M.P., Crawford, C.W., Pines, A., Wemmer, D.E., Knappe, S., Kitching, J. and Budker, D. “Optical detection of scalar coupling at zero magnetic field” J Magn Res. 199, 25-29 (2009). Buhrlage, S.J., Bates, C.A., Rowe, S.P., Minter, A.R., Brennan, B.B., Majmudar, C.Y., Wemmer, D.E., Al-Hashimi, H. and Mapp, A.K. “Small molecule transcriptional activation domains interact with endogenous coactivators” ACS Chem Bio 4, 335-344 (2009). Batchelor, J.D., Doucleff, M. Lee, C.J., Matsubara, K., DeCarlo, S., Heideker, J., Lamers, M.H., Pelton, J.G., Wemmer, D.E. “Structure and regulatory mechansim of A. aeolicus NtrC4: variability and evolution in bacterial transcriptional regulation” J. Molec. Biol. 384, 1058-75 (2008). Schröder, L., Chavez, L., Meldrum, T., Smith, M., Lowery, T.J., Wemmer, D.E. and Pines, A. “Temperature-Controlled Molecular Depolarization Gates in Nuclear Magnetic Resonance” Angew. Chem. Int Ed Engl 47, 4316-20 (2008). Schröder, L., Meldrum, T., Smith, M., Lowery, T.J., Wemmer, D.E. and Pines, A. “Temperature response of 129Xe depolarization transfer and application for unltra-sensitive NMR detection” Phys. Rev. Letters. 100: 257603 (2008) Fawzi, N.L., Phillips, A., Ruscio, J.Z., Doucleff, M., Wemmer, D.E. and Head-Gordon, T. “Structure and Dynamics of the Ab21-30 Peptide from the Interplay of NMR Experiments and Molecular Simulations.” J. Am. Chem. Soc. 130, 6145-58 (2008). Baxter, N.J., Blackburn, G.M., Marston, J.P., Hounslow, A.M., Cliff, M.J., Bermel, W., Hollfelder, F., Williams, N.H., Wemmer, D.E., Waltho, J.P. “Anionic Charge is Prioritized over Geometry in Aluminum and Magnesium Fluroide Transition State Analogs of Phosphoryl Transfer Enzymes” J. Am. Chem. Soc. 130, 3952-58 (2008). Lowery, T.J., Pelton, J.G., Chandonia, J.-M., Kim, R., Yokota, H., Wemmer, D.E. “NMR Structure of the N-terminal domain of the replication initiator protein DnaA” J. Str. Funct. Genomics 8, 11-17 (2007). Matsuda, S., Fillo, J.D., Henry, A.A., Wilkens, S.J., Rai, P., Dwyer, T.J., Beierstanger, B.H., Wemmer, D.E., Schultz, P.G., Spraggon, G., Romesberg, F.E., “Efforts Toward Expansion of the Genetic Alphabet: Determinants of Efficient Replication of Unnatural Base Pairs” J. Am. Chem. Soc. 129, 10466-73 (2007).