Biochemical studies have shown that domain 5 of the TrkA (tropomyosin receptor kinase A) receptor is involved in the binding of NGF (nerve growth factor). Crystallographic studies have confirmed this, demonstrating that one homodimer of NGF binds to two TrkAd5 molecules. TrkAd5 has been made recombinantly in Escherichia coli, purified and shown to bind NGF with picomolar affinity. We have used the co-ordinates of the crystal structure of the NGF–TrkAd5 complex to screen approximately two million compounds in silico for the identification of small molecule agonists/antagonists. Selected hits were shown to be active in an in vitro ligand-binding assay; structure–activity relationships are now being investigated. In addition, TrkAd5 has been shown to be efficacious in preclinical models of inflammatory pain and asthma by the sequestration of excess levels of endogenous NGF, and therefore represents a novel therapeutic agent.
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August 2006
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Conference Article|
July 21 2006
NGF receptor TrkAd5: therapeutic agent and drug design target
D. Dawbarn;
D. Dawbarn
1
*Department of Medicine, University of Bristol, Bristol BS1 3NY, U.K.
1To whom correspondence should be addressed (email dave.dawbarn@bristol.ac.uk).
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M. Fahey;
M. Fahey
*Department of Medicine, University of Bristol, Bristol BS1 3NY, U.K.
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J. Watson;
J. Watson
*Department of Medicine, University of Bristol, Bristol BS1 3NY, U.K.
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S. Tyler;
S. Tyler
*Department of Medicine, University of Bristol, Bristol BS1 3NY, U.K.
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D. Shoemark;
D. Shoemark
*Department of Medicine, University of Bristol, Bristol BS1 3NY, U.K.
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R. Sessions;
R. Sessions
†Department of Biochemistry, University of Bristol, Bristol BS1 3NY, U.K.
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R. Zhang;
R. Zhang
‡Department of Chemistry, University of Bristol, Bristol BS1 3NY, U.K.
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L. Brady;
L. Brady
†Department of Biochemistry, University of Bristol, Bristol BS1 3NY, U.K.
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C. Willis;
C. Willis
‡Department of Chemistry, University of Bristol, Bristol BS1 3NY, U.K.
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S.J. Allen
S.J. Allen
*Department of Medicine, University of Bristol, Bristol BS1 3NY, U.K.
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Publisher: Portland Press Ltd
Received:
April 26 2006
Online ISSN: 1470-8752
Print ISSN: 0300-5127
© 2006 The Biochemical Society
2006
Biochem Soc Trans (2006) 34 (4): 587–590.
Article history
Received:
April 26 2006
Citation
D. Dawbarn, M. Fahey, J. Watson, S. Tyler, D. Shoemark, R. Sessions, R. Zhang, L. Brady, C. Willis, S.J. Allen; NGF receptor TrkAd5: therapeutic agent and drug design target. Biochem Soc Trans 1 August 2006; 34 (4): 587–590. doi: https://doi.org/10.1042/BST0340587
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