Biological NMR spectroscopy^has reached an exciting stage, (i) Structures of small proteins can be solved rapidly with current technologies. In fact the collaborators on this PO1 grant have determined 28 structures of systems up to 35 kDa over the last five years, many of them supported by this grant, (ii) New NMR methods have emerged that have only partially utilized but promise a dramatic boost of speed, quality and quantity of structure studies, (iii) New hardware has arrived that can increase the sensitivity of spectrometers about fourfold, an unprecedented """"""""quantum leap"""""""" which will make it possible to tackle large and difficult structural problems of high significance. At this point, NMR is not so much limited by technology; the main challenge is producing, in a useable form, biological samples that we want to study for biological reasons. Thus, the goals of the proposed research are three fold. First, continueto improve NMR and computational methods (comp. 1, Wagner). Second, improve methods for expressing difficult isotope-labeled proteins in large quantities suitable for NMR experiments (comp. 2, Wagner). Third, this effort will be shared and applied to studies of large systems containing DNA repair proteins (comp. 4, Verdine), and as a challenging and medically important system, we will pursue a structural study of the bacterial EntF protein of 142 kDa (comp. 3, Walsh). The collaborators on this grant provide the expertise in NMR and computational methods, and in the production of biological molecules. They have a long history of collaboration and their group members share the laboratories whenever needed. Infrastructure support will be provided by three Cores. Core A (Administration), to be managed by G. Wagner, will provide administrative support to all participants . Core B (NMR Technology). also managed by G. Wagner, will make recent developments in NMR technology available for use in the above projects. Core C (Computation and Networking),managed by J. Hoch, will provide expertise state-of-the-art computing and networking environment.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Program Projects (P01)
Project #
3P01GM047467-16S1
Application #
7433046
Study Section
Special Emphasis Panel (ZRG1-BCMB-P (40))
Program Officer
Wehrle, Janna P
Project Start
1997-05-01
Project End
2012-04-30
Budget Start
2007-05-01
Budget End
2008-04-30
Support Year
16
Fiscal Year
2007
Total Cost
$9,760
Indirect Cost
Name
Harvard University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
047006379
City
Boston
State
MA
Country
United States
Zip Code
02115
Brazin, Kristine N; Mallis, Robert J; Boeszoermenyi, Andras et al. (2018) The T Cell Antigen Receptor ? Transmembrane Domain Coordinates Triggering through Regulation of Bilayer Immersion and CD3 Subunit Associations. Immunity 49:829-841.e6
Chhabra, Sandeep; Fischer, Patrick; Takeuchi, Koh et al. (2018) 15N detection harnesses the slow relaxation property of nitrogen: Delivering enhanced resolution for intrinsically disordered proteins. Proc Natl Acad Sci U S A 115:E1710-E1719
Zhao, Zhao; Zhang, Meng; Hogle, James M et al. (2018) DNA-Corralled Nanodiscs for the Structural and Functional Characterization of Membrane Proteins and Viral Entry. J Am Chem Soc 140:10639-10643
Hagn, Franz; Nasr, Mahmoud L; Wagner, Gerhard (2018) Assembly of phospholipid nanodiscs of controlled size for structural studies of membrane proteins by NMR. Nat Protoc 13:79-98
Nasr, Mahmoud L; Wagner, Gerhard (2018) Covalently circularized nanodiscs; challenges and applications. Curr Opin Struct Biol 51:129-134
Coote, Paul W; Robson, Scott A; Dubey, Abhinav et al. (2018) Optimal control theory enables homonuclear decoupling without Bloch-Siegert shifts in NMR spectroscopy. Nat Commun 9:3014
Ziarek, Joshua J; Baptista, Diego; Wagner, Gerhard (2018) Recent developments in solution nuclear magnetic resonance (NMR)-based molecular biology. J Mol Med (Berl) 96:1-8
Näär, Anders M (2018) miR-33: A Metabolic Conundrum. Trends Endocrinol Metab 29:667-668
Hyberts, Sven G; Robson, Scott A; Wagner, Gerhard (2017) Interpolating and extrapolating with hmsIST: seeking a tmax for optimal sensitivity, resolution and frequency accuracy. J Biomol NMR 68:139-154
Nasr, Mahmoud L; Baptista, Diego; Strauss, Mike et al. (2017) Covalently circularized nanodiscs for studying membrane proteins and viral entry. Nat Methods 14:49-52

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