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TitleDissecting NGF interactions with TrkA and p75 receptors by structural and functional studies of an anti-NGF neutralizing antibody.
Journal, issue, pagesJ Mol Biol, Vol. 381, Issue 4, Page 881-896, Year 2008
Publish dateSep 12, 2008
AuthorsSonia Covaceuszach / Alberto Cassetta / Petr V Konarev / Stefania Gonfloni / Rainer Rudolph / Dmitri I Svergun / Doriano Lamba / Antonino Cattaneo /
PubMed AbstractThe anti-nerve growth factor (NGF) monoclonal antibody alphaD11 is a potent antagonist that neutralizes the biological functions of its antigen in vivo. NGF antagonism is expected to be a highly ...The anti-nerve growth factor (NGF) monoclonal antibody alphaD11 is a potent antagonist that neutralizes the biological functions of its antigen in vivo. NGF antagonism is expected to be a highly effective and safe therapeutic approach in many pain states. A comprehensive functional and structural analysis of alphaD11 monoclonal antibody was carried out, showing its ability to neutralize NGF binding to either tropomyosine receptor kinase A (TrkA) or p75 receptors. The 3-D structure of the alphaD11 Fab fragment was solved at 1.7 A resolution. A computational docking model of the alphaD11 Fab-NGF complex, based on epitope mapping using a pool of 44 NGF mutants and experimentally validated by small-angle X-ray scattering, provided the structural basis for identifying the residues involved in alphaD11 Fab binding. The present study pinpoints loop II of NGF to be an important structural determinant for NGF biological activity mediated by TrkA receptor.
External linksJ Mol Biol / PubMed:18635195
MethodsSAS (X-ray synchrotron) / X-ray diffraction
Resolution1.7 Å
Structure data

SASDAS5:
ad11 Fab (aD11 Fab, Fab)
Method: SAXS/SANS

SASDAT5:
NGF
Method: SAXS/SANS

SASDAU5:
ad11 Fab + NGF (aD11 Fab, Fab + NGF)
Method: SAXS/SANS

PDB-1zan:
Crystal structure of anti-NGF AD11 Fab
Method: X-RAY DIFFRACTION / Resolution: 1.7 Å

Chemicals

ChemComp-CL:
Unknown entry

ChemComp-HOH:
WATER

Source
  • Mus musculus (house mouse)
  • rattus norvegicus (Norway rat)
KeywordsIMMUNE SYSTEM / Immunoglobulin / Fab

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