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J. Biol. Chem., Vol. 282, Issue 6, 4085-4093, February 9, 2007

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Protein Engineering of the Colony-stimulating Factor-1 Receptor Kinase Domain for Structural Studies^*

From the Structural Biology, Johnson & Johnson Pharmaceuticals Research and Development, L.L.C., Exton, Pennsylvania 19341

A parallel approach to designing crystallization constructs for the c-FMS kinase domain was implemented, resulting in proteins suitable for structural studies. Sequence alignment and limited proteolysis were used to identify and eliminate unstructured and surface-exposed domains. A small library of chimeras was prepared in which the kinase insert domain of FMS was replaced with the kinase insert domain of previously crystallized receptor-tyrosine kinases. Characterization of the newly generated FMS constructs by enzymology and thermoshift assays demonstrated similar activities and compound binding to the FMS full-length cytoplasmic domain. Two chimeras were evaluated for crystallization in the presence and absence of a variety of ligands resulting in crystal structures, and leading to a successful structure-based drug design project for this important inflammation target.

Received for publication, August 25, 2006 , and in revised form, November 3, 2006.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Structural Biology, Johnson & Johnson Pharmaceuticals Research and Development, L.L.C., 665 Stockton Dr., Exton, PA 19341. Tel.: 610-458-5264 x6574; Fax: 610-458-8249; E-mail: cschalkh{at}prdus.jnj.com.

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This article has been cited by other articles:

				C. Schubert, C. Schalk-Hihi, G. T. Struble, H.-C. Ma, I. P. Petrounia, B. Brandt, I. C. Deckman, R. J. Patch, M. R. Player, J. C. Spurlino, et al. Crystal Structure of the Tyrosine Kinase Domain of Colony-stimulating Factor-1 Receptor (cFMS) in Complex with Two Inhibitors J. Biol. Chem., February 9, 2007; 282(6): 4094 - 4101. [Abstract] [Full Text] [PDF]