The purpose of this Core is to provide a state-of-the-art NMR facility and medicinal chemistry expertise for the research in this program project grant. Both aspects are linked with each other and to the research components ofthe grant. The personnel will be responsible for keeping the NMR Facility and its instruments accessible, in optimal conditions, updated, and running without interruptions. The personnel will assure that existing and newly developed experimental techniques are made fully available to all participants and outside investigators on a 24-hour basis, 365 days of the year. This requires a very significant effort given the complexity and variation ofthe facility's instrumentation, and will be achieved through a close interaction between the director of the NMR facility, Gregory Heffron, and the PI, Gerhard Wagner via frequent meetings to discuss strategies for effective and economical operation ofthe lab which houses three 500's, two 600's, one 750, one 800, and the solution part of a 900 MHz instrument. In the coming months, a new Agilent 700MHz system with a high-sensitivity cryogenic probe will be installed and made available to the participants. Thus, the core is of central importance to this program project grant, and has demonstrated the ability to operate a highly productive NMR center with minimal downtime for nearly 20 years. In addition to supporting the NMR facility the Core will support specific research objectives in this grant by supporting high-throughput screening of ICCB compound libraries, NMR-based fragment screening and measuring inter-ligand NOEs of fragments, and the chemistry effort required to link fragments and optimize HTS hits or tethered compounds. In particular, these functions within the core will support discovery and optimization of inhibitors of the bacterial non-ribosomal peptide synthetase (Enterobactin Synthetase, Component 2),the TCR signaling component (Component 3), and the pleiotropic drug resistance mechanism of pathogenic yeasts (Component 4). Dr. Nathanael Gray at Dana Farber Cancer Institute, a world expert in discovery and optimization of kinase inhibitors and other drugs, will direct the medicinal chemistry effort on these projects. Nathanael Gray and his group routinely work with investigators at Dana-Farber Cancer Institute on all aspects of small molecule probe and drug discovery from hit identification following high throughput screening to developing advanced molecules highly optimized for potency, physical properties, in vitro DMPK, and in vivo PK.

Public Health Relevance

The NMR technology provided here is key to the entire research proposed here. It links the research components. The Medicinal Chemistry expertise provided by the Core will allow utilizing the structure information ofthe large systems to develop drugs for curing human diseases

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Research Program Projects (P01)
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Special Emphasis Panel (ZRG1)
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Harvard Medical School
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Takeuchi, Koh; Sun, Zhen-Yu J; Li, Shuai et al. (2015) NMR resonance assignments of the catalytic domain of human serine/threonine phosphatase calcineurin in unligated and PVIVIT-peptide-bound states. Biomol NMR Assign 9:201-5
Edmonds, Katherine A; Wagner, Gerhard (2015) (1)H, (13)C, and (15)N backbone and sidechain chemical shift assignments for the HEAT2 domain of human eIF4GI. Biomol NMR Assign 9:157-60
Hagn, Franz; Wagner, Gerhard (2015) Structure refinement and membrane positioning of selectively labeled OmpX in phospholipid nanodiscs. J Biomol NMR 61:249-60
Wommack, Andrew J; Ziarek, Joshua J; Tomaras, Jill et al. (2014) Discovery and characterization of a disulfide-locked C(2)-symmetric defensin peptide. J Am Chem Soc 136:13494-7
Boeszoermenyi, Andras; Schmidt, Jens C; Cheeseman, Iain M et al. (2014) Resonance assignments of the microtubule-binding domain of the C. elegans spindle and kinetochore-associated protein 1. Biomol NMR Assign 8:275-8
Akabayov, Sabine R; Akabayov, Barak; Wagner, Gerhard (2014) Human translation initiation factor eIF4G1 possesses a low-affinity ATP binding site facing the ATP-binding cleft of eIF4A in the eIF4G/eIF4A complex. Biochemistry 53:6422-5
Sun, Zhen-Yu J; Cheng, Yuxing; Kim, Mikyung et al. (2014) Disruption of helix-capping residues 671 and 674 reveals a role in HIV-1 entry for a specialized hinge segment of the membrane proximal external region of gp41. J Mol Biol 426:1095-108
Hoch, Jeffrey C; Maciejewski, Mark W; Mobli, Mehdi et al. (2014) Nonuniform sampling and maximum entropy reconstruction in multidimensional NMR. Acc Chem Res 47:708-17
Brazin, Kristine N; Mallis, Robert J; Li, Chen et al. (2014) Constitutively oxidized CXXC motifs within the CD3 heterodimeric ectodomains of the T cell receptor complex enforce the conformation of juxtaposed segments. J Biol Chem 289:18880-92
Linser, Rasmus; Bardiaux, Benjamin; Andreas, Loren B et al. (2014) Solid-state NMR structure determination from diagonal-compensated, sparsely nonuniform-sampled 4D proton-proton restraints. J Am Chem Soc 136:11002-10

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