Structural Genomics Center for Infectious Diseases - Year III
EMSL Project ID
41092
Abstract
New medicines are urgently needed against infectious diseases that are becoming increasingly more resistant to current therapies. The strategy being used by the National Institute of Health (NIH) to discover new drugs is to target a wide range of pathogen proteins shown to be involved in pathogenesis (virulence factors), drug resistance, or cell survival. These protein targets have been selected because they are expected to have an important biological role and potential impact on biomedical research. Presently, structure-based drug design is playing a growing role in modern drug discovery with many of the latest approved drugs tracing their origins, at least in part, to structural information provided by X-ray diffraction (XRD) or nuclear magnetic resonance (NMR) analyses. Consequently, a major objective of NIH towards discovering new antimicrobial drugs is to determine the three-dimensional atomic structures for these protein targets and their ligand bound complexes in a high-throughput fashion. Such information will be made available to the scientific community and serve as the blueprints for structure-based drug discovery. While X-ray diffraction methods are the primary means of structure solution in high-throughput modes, not all proteins crystallize or produce well-diffracting crystals. In these instances structure solution will be rescued by NMR-based methods using the suite of NMR spectrometers at EMSL. In addition to rescuing the structure solution of difficult targets, NMR spectroscopy, circular dichroism spectroscopy and isothermal titration calorimetry will be used to identify new ligands that bind to the targets and to study the mechanistic details of the biological function of the targets.
Project Details
Project type
Exploratory Research
Start Date
2010-07-27
End Date
2011-08-07
Status
Closed
Released Data Link
Team
Principal Investigator
Team Members
Related Publications
Solution-state NMR structure of the putative morphogene protein BolA (PFE0790c) fromPlasmodium falciparum
Buchko GW, A Yee, A Semesi, PJ Myler, CH Arrowsmith, and R Hui. 2015. "Solution-state NMR structure of the putative morphogene protein BolA (PFE0790c) from Plasmodium falciparum." Acta Crystallographica. Section F F71(5):514-521. doi: 10.1107/S2053230X1402799X
Structure of a CutA1 divalent-cation tolerance protein fromCryptosporidium parvum, the protozoal parasite responsible for cryptosporidiosis
Buchko GW, J Abendroth, MC Clifton, H Robinson, Y Zhang, SN Hewitt, BL Staker, TE Edwards, WC Van Voorhis, and PJ Myler. 2015. "Structure of a CutA1 divalent-cation tolerance protein from Cryptosporidium parvum, the protozoal parasite responsible for cryptosporidiosis." Acta Crystallographica. Section F F71(5):522-530. doi:10.1107/S2053230X14028210
Increasing the structural coverage of tuberculosis drug targets
Baugh L, I Phan, DW Begley, MC Clifton, B Armour, DM Dranow, BM Taylor, MM Muruthi, J Abendroth, JW Fairman, D Fox III, SH Dieterich, BL Staker, AS Gardberg, R Choi, SN Hewitt, AJ Napuli, J Myers, L Barrett, Y Zhang, M Ferrell, E Mundt, K Thompkins, N Tran, S Lyons-Abbott, A Abramov, A Sekar, D Serbzhinskiy, D Lorimer, GW Buchko, R Stacy, LJ Stewart, TE Edwards, WC Van Voorhis, and PJ Myler. 2015. "Increasing the Structural Coverage of Tuberculosis Drug Targets ." Tuberculosis 95(2):142-148. doi:10.1016/j.tube.2014.12.003
Combining Functional and Structural Genomics to Sample the Essential Burkholderia Structome
Baugh L, LA Gallagher, R Patrapuvich, MC Clifton, AS Gardberg, TE Edwards, B Armour, DW Begley, SH Dieterich, DM Dranow, J Abendroth, JW Fairman, D Fox III, BL Staker, I Phan, A Gillespie, R Choi, S Nakazawa-Hewitt, MT Nguyen, AJ Napuli, L Barrett, GW Buchko, R Stacy, PJ Myler, LJ Stewart, C Manoil, and WC Van Voorhis. 2013. "Combining Functional and Structural Genomics to Sample the Essential Burkholderia Structome." PLoS One 8(1):e53851. doi:10.1371/journal.pone.0053851
Chemical shift assignments for Rv0577, a putative glyoxylase associated with virulence from Mycobacterium tuberculosis
Buchko GW, H Kim, PJ Myler, TC Terwilliger, and CY Kim. 2012. "Chemical shift assignments for Rv0577, a putative glyoxylase associated with virulence from Mycobacterium tuberculosis ." Biomolecular NMR Assignments 6(1):43-46. doi:10.1007/s12104-011-9322-5
Structural Genomics-A Goldmine of Blueprints for Structure-Based Drug Design
Buchko GW. 2011. "Structural genomics - A goldmine of blueprints for structure-based drug design." Metabolomics 1(2):104e. doi:10.4172/2153-0769.1000104e
Solution structure of an arsenate reductase-related protein, YffB, fromBrucella melitensis, the etiological agent responsible for brucellosis
Buchko GW, SN Hewitt, AJ Napuli, WC Van Voorhis, and PJ Myler. 2011. "Solution structure of an arsenate reductase-related protein, YffB, from Brucella melitensis, the etiological agent responsible for brucellosis." Acta Crystallographica. Section F F67(9):1129-1136. doi:10.1107/S1744309111006336
Solution-state NMR structure and biophysical characterization of zinc-substituted rubredoxin B (Rv3250c) fromMycobacterium tuberculosis
Buchko GW, SN Hewitt, AJ Napuli, WC Van Voorhis, and PJ Myler. 2011. "Solution-state NMR structure and biophysical characterization of zinc-substituted rubredoxin B (Rv3250c) from Mycobacterium tuberculosis." Acta Crystallographica. Section F F67(9):1148-1153. doi:10.1107/S1744309111008189
Inaugural structure from the DUF3349 superfamily of proteins, Mycobacterium tuberculosis Rv0543c
Buchko GW, I Phan, PJ Myler, TC Terwilliger, and CY Kim. 2011. "Inaugural structure from the DUF3349 superfamily of proteins, Mycobacterium tuberculosis Rv0543c." Archives of Biochemistry and Biophysics 506(2):150-156. doi:10.1016/j.abb.2010.12.001