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| Structural Biology: X-ray Crystallography and NMR Spectroscopy |
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| Objective: |
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To develop and apply measurement methods, databases, and state-of- the-art modeling methods to advance the understanding of protein structure/function relationships. |
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| Description: |
| CSTL and University of Maryland researchers are working in the area of structural biology at the Center for Advanced Research in Biotechnology located on Shady Grove road near the NIST Gaithersburg main campus. Researchers use many tools to determine protein structure and understand their function. X-ray crystallography and NMR methods are used to determine the structures of proteins, complexes, and other macromolecular systems Calorimetry and fluorimetry are utilized to understand protein function in terms of thermodynamic parameters. Bioinfomatics approaches in genomics are also being utilized to understand the evolution of structure and function changes in proteins.
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| Area(s) of Application: |
- Pharmaceuticals
- Health and Medical Products and Services
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| Accomplishments: |
- X-ray Crystallography Databases play an important role in drug discovery and in biotechnology and biological research. Current activities involve the NIST/CARB Biological Macromolecule Crystallization Database ( http://wwwbmcd.nist.gov:8080/bmcd/bmcd.html ) and the NASA Archive for Protein Crystal Growth Data
- Nuclear magnetic resonance (NMR) techniques are being applied to determine the structure and dynamics of proteins, nucleic acids and protein-nucleic acids complexes in solution. Efforts include the development of new multi-dimensional heteronuclear NMR methods for resonance assignment, J-coupling constant and residual dipolarcoupling determination, and ligand screening. High-resolution structures and information about macromolecular dynamics determined using NMR methods are being applied to accelerate the discovery of novel therapeutics that target retroviral RNA.
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| Future Plans: |
- High throughput screening of potential drugs that inhibit the retrovirus RNA-protein interactions critical to the spread of AIDSexpression of the HIV-1 protease responsible for AIDS.
- Characterize how potential drugs inhibit retrovirus RNA-protein interactions to facilitate rational drug design.
- Determine how single DNA and RNA conformations affect hybridization processes.
- Setup a laboratory for research in proteomics mass spectrometry
- Develop software tools to validate models of protein mutations that are responsible for gene diversity and inherited diseases.
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| Recent publications: |
- G. L. Gilliland, M. Tung, J. E. Ladner, “The Biological Macromolecule Crystallization Database: Crystallization Procedures and Strategies”. Acta Cryst. D 2002, 58, 916-920.2. M. R. Mihailescu,J. P. Marino “A proton-coupled dynamic conformational switch in the HIV-1 dimerization initiation site kissing complex”, Proc. Natl. Acad. Sci., U.S.A.., 2004, 101, 1189-1194.
- T. D. Bradrick, J. P. Marino, “Ligand-induced changes in 2-aminopurine fluorescence as a probe for small molecule binding to HIV-1 TAR RNA,” RNA 2004, 10, 1459-1468.
- Luy, J. P. Marino, “JE-TROSY: combined J- and TROSY-spectroscopy for the Measurement of One-bond Couplings in Macromolecules,” J. Magn. Reson. 2003, 163, 92-98.
- E.S. DeJong, B. Luy, J. P. Marino, “Applications of NMR and Fluorescence in RNA Targeted Drug Design,” Curr. Top. Med. Chem. (2002) 2, 289-302.
- B. Luy, U. Richter, E. S. DeJong, O. W. Sørensen, J. P. Marino, “Observation of H-bond Mediated 3h J H2H3 Couplings across Watson-Crick AU Base Pairs in RNA,” J. Biomol. NMR 2002, 24, 133-142
- M. Stodeman, F. P. Schwarz, “Importance of Product/Substrate Equilibrium in the Kinetics of the Phosphoglucose Isomerization Reaction by Differential Stopped Flow Microcalorimetry,” Anal. Biochem 2004, 329, 307-315.
- S. Krueger, S. Gregurick, Y. Shi, S. Wang, B. D. Wladkowski, F. P. Schwarz, “Entropic Nature of the Interaction Between Promoter Bound CRP Mutants and RNA Polymerase,” Biochemistry 42, 2003, 1958-1968.
- L.Y. Yampolsky, A. Stoltzfus “Amino acid exchangeability from experimental data”, Genetics, 2005, submitted.
- Stoltzfus., Molecular Evolution: Introns Fall into Place. Curr. Biol. 2004, 14, R351-352.
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