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Science 9 May 1997:
Vol. 276. no. 5314, pp. 955 - 960
DOI: 10.1126/science.276.5314.955
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Reports

Structures of the Tyrosine Kinase Domain of Fibroblast Growth Factor Receptor in Complex with Inhibitors

Moosa Mohammadi, Gerald McMahon, Li Sun, Cho Tang, Peter Hirth, Brian K. Yeh, Stevan R. Hubbard, * Joseph Schlessinger *

A new class of protein tyrosine kinase inhibitors was identified that is based on an oxindole core (indolinones). Two compounds from this class inhibited the kinase activity of fibroblast growth factor receptor 1 (FGFR1) and showed differential specificity toward other receptor tyrosine kinases. Crystal structures of the tyrosine kinase domain of FGFR1 in complex with the two compounds were determined. The oxindole occupies the site in which the adenine of adenosine triphosphate binds, whereas the moieties that extend from the oxindole contact residues in the hinge region between the two kinase lobes. The more specific inhibitor of FGFR1 induces a conformational change in the nucleotide-binding loop. This structural information will facilitate the design of new inhibitors for use in the treatment of cancer and other diseases in which cell signaling by tyrosine kinases plays a crucial role in disease pathogenesis.

M. Mohammadi, B. K. Yeh, J. Schlessinger, Department of Pharmacology, New York University Medical Center, New York, NY 10016, USA.
G. McMahon, L. Sun, C. Tang, P. Hirth, SUGEN, Redwood City, CA 94063, USA.
S. R. Hubbard, Skirball Institute of Biomolecular Medicine and Department of Pharmacology, New York University Medical Center, New York, NY 10016, USA.
*   To whom correspondence should be addressed.

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Fibroblast growth factor-1 improves cardiac functional recovery and enhances cell survival after ischemia and reperfusion: A fibroblast growth factor receptor, protein kinase c, and tyrosine kinase-dependent mechanism.
M. Palmen, M. J.A.P. Daemen, L. J. De Windt, J. Willems, W. R.M. Dassen, S. Heeneman, R. Zimmermann, M. Van Bilsen, and P. A. Doevendans (2004)
J. Am. Coll. Cardiol. 44, 1113-1123
   Abstract »    Full Text »    PDF »
The development of semicircular canals in the inner ear: role of FGFs in sensory cristae.
W. Chang, J. V. Brigande, D. M. Fekete, and D. K. Wu (2004)
Development 131, 4201-4211
   Abstract »    Full Text »    PDF »
The Fgf8 signal causes cerebellar differentiation by activating the Ras-ERK signaling pathway.
T. Sato and H. Nakamura (2004)
Development 131, 4275-4285
   Abstract »    Full Text »    PDF »
Signalling by the FGFR-like tyrosine kinase, Kringelchen, is essential for bud detachment in Hydra vulgaris.
S. Sudhop, F. Coulier, A. Bieller, A. Vogt, T. Hotz, and M. Hassel (2004)
Development 131, 4001-4011
   Abstract »    Full Text »    PDF »
Screening of FGF target genes in Xenopus by microarray: temporal dissection of the signalling pathway using a chemical inhibitor.
H. A. Chung, J. Hyodo-Miura, A. Kitayama, C. Terasaka, T. Nagamune, and N. Ueno (2004)
Genes Cells 9, 749-761
   Abstract »    Full Text »    PDF »
Developmental Regulation of Gonadotropin-Releasing Hormone Neurons by Fibroblast Growth Factor Signaling.
J. C. Gill, S. M. Moenter, and P.-S. Tsai (2004)
Endocrinology 145, 3830-3839
   Abstract »    Full Text »    PDF »
Combinatorial Fgf and Bmp signalling patterns the gastrula ectoderm into prospective neural and epidermal domains.
T. Kudoh, M. L. Concha, C. Houart, I. B. Dawid, and S. W. Wilson (2004)
Development 131, 3581-3592
   Abstract »    Full Text »    PDF »
Fgf3 signaling from the ventral diencephalon is required for early specification and subsequent survival of the zebrafish adenohypophysis.
W. Herzog, C. Sonntag, S. von der Hardt, H. H. Roehl, Z. M. Varga, and M. Hammerschmidt (2004)
Development 131, 3681-3692
   Abstract »    Full Text »    PDF »
Determination of embryonic polarity in a regulative system: evidence for endogenous inhibitors acting sequentially during primitive streak formation in the chick embryo.
F. Bertocchini, I. Skromne, L. Wolpert, and C. D. Stern (2004)
Development 131, 3381-3390
   Abstract »    Full Text »    PDF »
FGF signaling is required for initiation of feather placode development.
M. Mandler and A. Neubuser (2004)
Development 131, 3333-3343
   Abstract »    Full Text »    PDF »
Mouse limb deformity mutations disrupt a global control region within the large regulatory landscape required for Gremlin expression.
A. Zuniga, O. Michos, F. Spitz, A.-P. G. Haramis, L. Panman, A. Galli, K. Vintersten, C. Klasen, W. Mansfield, S. Kuc, et al. (2004)
Genes & Dev. 18, 1553-1564
   Abstract »    Full Text »    PDF »
Fgf signalling controls the dorsoventral patterning of the zebrafish embryo.
M. Furthauer, J. Van Celst, C. Thisse, and B. Thisse (2004)
Development 131, 2853-2864
   Abstract »    Full Text »    PDF »
Tyrosine Phosphorylation of Sprouty Proteins Regulates Their Ability to Inhibit Growth Factor Signaling: A Dual Feedback Loop.
J. M. Mason, D. J. Morrison, B. Bassit, M. Dimri, H. Band, J. D. Licht, and I. Gross (2004)
Mol. Biol. Cell 15, 2176-2188
   Abstract »    Full Text »    PDF »
Protein Kinase Inhibitors: Insights into Drug Design from Structure.
M. E. M. Noble, J. A. Endicott, and L. N. Johnson (2004)
Science 303, 1800-1805
   Abstract »    Full Text »    PDF »
Nodal and Fgf pathways interact through a positive regulatory loop and synergize to maintain mesodermal cell populations.
J. Mathieu, K. Griffin, P. Herbomel, T. Dickmeis, U. Strahle, D. Kimelman, F. M. Rosa, and N. Peyrieras (2004)
Development 131, 629-641
   Abstract »    Full Text »    PDF »


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