Journal of Structural and Functional Genomics

, Volume 8, Issue 4, pp 193–198 | Cite as

Development of an alternative approach to protein crystallization

  • Alexander McPherson
  • Chieniang Nguyen
  • Steven B. Larson
  • John S. Day
  • Bob Cudney


We are developing an alternate strategy for the crystallization of macromolecules that does not, like current methods, depend on the optimization of traditional variables such as pH and precipitant concentration, but is based on the hypothesis that many conventional small molecules might establish stabilizing, intermolecular, non covalent crosslinks in crystals, and thereby promote lattice formation. To test the hypothesis, we carried out preliminary experiments encompassing 18,240 crystallization trials using 81 different proteins, and 200 chemical compounds. Statistical analysis of the results demonstrated the validity of the idea. In addition, we conducted X-ray diffraction analyses of some of the crystals grown in the experiments. These clearly showed incorporation of conventional molecules into the protein crystal lattices, and further validated the underlying hypothesis. We are currently extending the investigations to include a broader and more diverse set of proteins, an expanded search of conventional and biologically active small molecules, and a wider range of precipitants. The strategy proposed here is essentially orthogonal to current approaches and has an objective of doubling the success rate of today.


Additives Cross-links Evaluation Lattice Screening X-ray diffraction 



Polyethylene glycol


Deoxy guanosine monophosphate

RNase A

Ribonuclease A



This work was supported by NIH grant GM074899 for the establishment of the Center for High Throughput Structural Biology, and by Hampton Research, Aliso Viejo, CA.


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Copyright information

© Springer Science+Business Media B.V. 2007

Authors and Affiliations

  • Alexander McPherson
    • 1
  • Chieniang Nguyen
    • 2
  • Steven B. Larson
    • 1
  • John S. Day
    • 1
  • Bob Cudney
    • 2
  1. 1.Department of Molecular Biology and BiochemistryUniversity of CaliforniaIrvineUSA
  2. 2.Hampton Research CorporationAliso ViejoUSA

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