Every time science develops a major new tool, the first impressions of what it will reveal and enable are always inadequate. Even in the first few years of our Center projects have emerged that no one visualized all. But here is one possible long-term impact that expands the realm of drug design.
A Deeper Understanding
I direct a multi-institutional center, funded by the NSF, that seeks to use x-ray lasers to transform the way x-ray crystallography makes images of biological molecules such as proteins. A key outcome will be “molecular movies” that reveal how proteins changes their structures or shapes as they go through a functional cycle. At this moment there are only two operational x-ray lasers in the world, and the Linac Coherent Light Source at Stanford is the more advanced of these. Our work is dominated by the development of new technologies that allow new classes of experiments to be carried out at the x-ray laser. This very much a frontier project. Most drugs work by binding to a protein molecule, making a kind of lock-and-key complex that alters how the protein functions. The “lock” in this analogy is the protein, and we implicitly assume that the lock has a single structure. Picture of protein “locks” come from the HWI field of crystallography. But in fact as proteins pass through a functional cycle they move (change shape), and every snapshot along the path of motion presents a different “lock” for which we could created a different “key” or drug molecule. These pictures would come from the molecular movies mentioned above.-
Sol Gruner and Eaton Lattman. Biostructural Science Inspired by Next-generation X-ray Sources. Ann. Rev. Bioph. 44, 33-51, (2015).
A. Aquila, A. Barty, C. Bostedt, S. Boutet, G. Carini, D. dePonte, P. Drell, S. Doniach, K. H. Downing, T. Earnest, H. Elmlund, V. Elser, M. Gühr, J. Hajdu, J. Hastings, S. P. Hau-Riege, Z. Huang, E. E. Lattman, F. R. N. C. Maia, S. Marchesini, A. Ourmazd, C. Pellegrini, R. Santra, I. Schlichting, C. Schroer, J. C. H. Spence, I. A. Vartanyants, S. Wakatsuki, W. I. Weis and G. J. Williams. The Linac Coherent Light Source Single Particle Road Map. Structural Dynamics , 041701 (2015); doi: 10.1063/1.4918726.
Eaton Lattman and David DeRosier. Why Phase Errors Affect the Electron Density Function More Than Amplitude Errors. Acta Cryst. A64, 341-344 (2008).
Eaton E. Lattman. Molecular Structures From Femtosecond X-Ray Pulses. Proc. Natl. Acad. Sci. 98, 6535-6 (2001).
Jay L. Jeong, Eaton E. Lattman, and Gregory S. Chirikjian. A method for finding candidate conformations for molecular replacement using relative rotation between domains of a known structure. Acta Cryst. D62, 398-409 (2006).
Eaton E. Lattman. The Planck Length As The Dimension Of A Transient Black Hole. Eur. J. Phys. 30, L41-L42 (2009).
Eaton E. Lattman and Patrick J. Loll. X-ray Crystallography: A Concise Guide. Johns Hopkins Press: Baltimore, MD. (2008).
Eaton E. Lattman. Optimal Sampling of the Rotation Function in The Molecular Replacement Method, pp. 179-183, M. Rossmann, Ed., Gordon and Breach, New York City, (1972).
Eaton E. Lattman. Optimal Sampling of the Rotation Function. Acta Cryst. B28, 1065-1068 (1972).
Eaton E. Lattman and Warner E. Love. A Rotational Search Procedure for Detecting a Known Molecule in a Crystal. Acta Cryst. B26, 1854-1857 (1970).
Wayne A. Hendrickson and Eaton E. Lattman. Representation of Phase Probability Distributions for Simplified Combination of Independent Phase Information. Acta Cryst. B26, 136-143 (1970).
Our Research Group
Eaton E. Lattman, PhD
T: 716 898 8612