Robert London, Ph.D.
Genome Integrity & Structural Biology Laboratory / Nuclear Magnetic Resonance Group
Building 101, Room MRI08
111 T.W. Alexander Drive
Research Triangle Park, NC 27709
The ability of cells to function and to survive is dependent on biological catalysts that facilitate the transformation of available nutrients into cellular components, metabolize fats and carbohydrates to obtain energy, and sustain a multitude of cellular functions. These catalysis are predominantly proteins ñ sequences of amino acids, that adopt three dimensional structures allowing them to recognize their target substrate molecules, and to optimize the conversion of the target to a specific product with extremely high efficiency. Determining the three dimensional shapes of these biological catalysts is an essential step in understanding their function. For catalytic enzymes, this determination reveals the structural and functional significance of each component amino acid. This information is central to understanding how this function can be impaired in various disease states, or in the presence of harmful environmental agents.
The technique of nuclear magnetic resonance (NMR) provides the most detailed method for characterizing the structure and chemical properties of these biological catalysts in solution. The nuclei of each atom in a biomolecule such as a protein or DNA produces distinct resonances that provide information on the local environment of that nucleus. This information provides a wealth of insight into the structural, dynamic, and chemical characteristics of that nucleus. This information also allows researchers to investigate the interactions of these molecules with other cellular components and with exogenous agents that may interfere with the normal function.
The Nuclear Magnetic Resonance (NMR) Group is a technique-based research group that utilizes principally the NMR method to characterize the structural, conformational and dynamic responses of these biomolecular catalysts to substrates, cofactors, allosteric effectors, other proteins, putative environmental toxins, nucleic acids, etc. The nuclei of each atom in a biomolecule such as a protein or DNA produces distinct resonances that provide information on the local environment of that nucleus. This information provides a wealth of insight into the structural, dynamic, and chemical characteristics of that nucleus. This information also allows researchers to investigate the interactions of these molecules with other cellular components and with exogenous agents that may interfere with the normal function.
Over the past decade, many of these studies have targeted proteins involved in DNA repair in order to better understand the mechanisms that underlie polymerase fidelity and mutagenesis. Generally, these enzymes do not act independently, functioning as components of a repair complex that recruits the required repair factors to the site of DNA damage and coordinates the activities of these enzymes. Data derived from NMR studies is typically integrated with data generated using other techniques, particularly X-ray crystallography and small angle X-ray scattering, in order to extend the range of molecular targets accessible to investigation.
With support from the AIDS targeted research program, another important focus of the group is the characterization of the viral reverse transcriptase (RT) enzyme, which represents an important drug target for the treatment of HIV infection. Recent studies have characterized the complex conformational behavior of RT, and the dimerization process which is required to obtain active enzyme. We are also investigating the Ribonuclease H domain of RT, since at present there are no drugs which specifically target the activity of this domain.
A third focus of our research effort has involved the structural characterization of major allergens. Determination of the structure represents an important step in understanding the basis for their allergenicity, and for the development of hypoallergenic analogs that can be used for desensitization. Recent successes include determination of dust mite, peanut, pollen, and cockroach allergens.
Dr. London received his PhD in physical biochemistry from the University of Illinois in 1973. He was subsequently a postdoctoral fellow and later a staff scientist in the Stable Isotopes (ICONS) Program of the Los Alamos National Laboratory. This program, which later received additional support from the NIH to form the National Stable Isotopes Resource, facilitated the introduction of stable isotopes of carbon, nitrogen, and oxygen in basic biochemical and biomedical research. Dr. London moved to the NIEHS in 1983 to become Principal Investigator of the NMR research group in the Laboratory of Molecular Biophysics, and subsequently the Laboratory of Structural Biology.
London RE. Theoretical analysis of the inter-ligand overhauser effect: a new approach for mapping structural relationships of macromolecular ligands. J Magn Reson. 1999;141(2):301-11.
Cuneo MJ, London RE. Oxidation state of the XRCC1 N-terminal domain regulates DNA polymerase beta binding affinity. Proc Natl Acad Sci U S A. 2010;107(15):6805-10.
Zheng X, Mueller GA, Cuneo MJ, Derose EF, London RE. Homodimerization of the p51 subunit of HIV-1 reverse transcriptase. Biochemistry. 2010;49(13):2821-33.
Kirby TW, DeRose EF, Cavanaugh NA, Beard WA, Shock DD, Mueller GA, Wilson SH, London RE. Metal-induced DNA translocation leads to DNA polymerase conformational activation. Nucleic Acids Res. 2012;40(7):2974-83.
Zheng X, Mueller GA, DeRose EF, London RE. Metal and ligand binding to the HIV-RNase H active site are remotely monitored by Ile556. Nucleic Acids Res. 2012;40(20):10543-53.