The overall objective of the proposed research is to effect a major enhancement in methods for macromolecular structure analysis. Recent advances demonstrate that anomalous scattering can be used for the straightforward determination of three-dimensional structure from a single macromolecular crystal. Realization of the full potential of the new methods requires further development in instrumentation, computational procedures, and biochemistry. These developments will be pursued in the context of analyzing particular crystals structures of biological significance. The overall objective is embodied in four specific aims: (1) We propose to continue our efforts to develop the theoretical basis and computational implementation of methods for exploiting the effects of anomalous scattering, particularly in multiwavelength anomalous diffraction (MAD) studies. (2) We propose to optimize the experimental procedures for conducting MAD experiments. For the most part these experiments will be conducted at the Hughes Synchrotron Resource that we are developing at Brookhaven National Laboratory. but we will also participate in the development of beamlines at other sources. (3) We propose to devise various means for introducing suitable scattering centers into macromolecules and to study the anomalous scattering characteristics of such centers. This work will emphasize general and convenient preparative procedures and especially strong scattering effects. (4) We propose to perform the methodology development in the course of applications to macromolecular crystal structures. Biologically exciting problems motivate the development of appropriate tools, and forefront methods accelerate the solution of interesting structures. Specific plans are described for studies on several systems of considerable biological and medical significance.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37GM034102-17
Application #
6180157
Study Section
Special Emphasis Panel (NSS)
Program Officer
Lewis, Catherine D
Project Start
1984-04-01
Project End
2004-05-31
Budget Start
2000-06-01
Budget End
2001-05-31
Support Year
17
Fiscal Year
2000
Total Cost
$342,545
Indirect Cost
Name
Columbia University (N.Y.)
Department
Physiology
Type
Schools of Medicine
DUNS #
167204994
City
New York
State
NY
Country
United States
Zip Code
10032
Hendrickson, Wayne A (2014) Anomalous diffraction in crystallographic phase evaluation. Q Rev Biophys 47:49-93
Zhang, Zhen; Liu, Qun; Hendrickson, Wayne A (2014) Crystal structures of apparent saccharide sensors from histidine kinase receptors prevalent in a human gut symbiont. FEBS J 281:4263-79
Liu, Qun; Liu, Qinglian; Hendrickson, Wayne A (2013) Robust structural analysis of native biological macromolecules from multi-crystal anomalous diffraction data. Acta Crystallogr D Biol Crystallogr 69:1314-32
Liu, Qun; Dahmane, Tassadite; Zhang, Zhen et al. (2012) Structures from anomalous diffraction of native biological macromolecules. Science 336:1033-7
Moore, Jason O; Hendrickson, Wayne A (2012) An asymmetry-to-symmetry switch in signal transmission by the histidine kinase receptor for TMAO. Structure 20:729-41
Martinez-Hackert, Erik; Hendrickson, Wayne A (2011) Structural analysis of protein folding by the long-chain archaeal chaperone FKBP26. J Mol Biol 407:450-64
Collins, Mark N; Hendrickson, Wayne A (2011) Structural characterization of the Boca/Mesd maturation factors for LDL-receptor-type ? propeller domains. Structure 19:324-36
Liu, Qun; Zhang, Zhen; Hendrickson, Wayne A (2011) Multi-crystal anomalous diffraction for low-resolution macromolecular phasing. Acta Crystallogr D Biol Crystallogr 67:45-59
Zhang, Zhen; Hendrickson, Wayne A (2010) Structural characterization of the predominant family of histidine kinase sensor domains. J Mol Biol 400:335-53
Moore, Jason O; Hendrickson, Wayne A (2009) Structural analysis of sensor domains from the TMAO-responsive histidine kinase receptor TorS. Structure 17:1195-204

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