Eph receptors are the largest family of receptor tyrosine kinases. Eph-RTKs and their ligands, ephrins, are predominantly expressed in the developing and adult nervous system and have a key role in axon guidance, fasciculation, and cell migration. The applicant proposes to characterize Eph-receptor/ephrin interactions, through crystallographic studies. The crystal structure of the ligand-binding domain of Eph-B2 (a class B receptor) has been determined, revealing a jelly-roll architecture related to the sialic- acid binding domain of flu HA. Crystallographic analyses of the class A Eph receptors and of both classes of ephrins are planned. The focus will be on identification of structural elements the contribute to receptor-ligand recognition and class (A/B) discrimination. Structures of complexes will also be analyzed. These comparative crystallographic studies will define the structural basis of the high promiscuity of Eph- RTK/ephrin interactions within the classes, but lack of cross- interaction between classes. The kinetics and thermodynamics of these interactions will also be determined.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS038486-02
Application #
6151629
Study Section
Biophysical Chemistry Study Section (BBCB)
Program Officer
Chiu, Arlene Y
Project Start
1999-02-01
Project End
2004-01-31
Budget Start
2000-02-01
Budget End
2001-01-31
Support Year
2
Fiscal Year
2000
Total Cost
$235,599
Indirect Cost
Name
Sloan-Kettering Institute for Cancer Research
Department
Type
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10065
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Xu, Kai; Xu, Yan; Rajashankar, Kanagalaghatta R et al. (2013) Crystal structures of Lgr4 and its complex with R-spondin1. Structure 21:1683-9
Nikolov, Dimitar B; Xu, Kai; Himanen, Juha P (2013) Eph/ephrin recognition and the role of Eph/ephrin clusters in signaling initiation. Biochim Biophys Acta 1834:2160-5

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