Reference 2

Nature 354: 411-4 (1991)[92065986] 

New protein fold revealed by a 2.3-A resolution crystal
structure of nerve growth factor.

N. Q. McDonald, R. Lapatto, J. Murray-Rust, J. Gunning, A. Wlodawer & T. L. Blundell

ICRF Unit for Structural Molecular Biology, Birkbeck College, London, UK. 

Nerve growth factor (NGF) is a member of an expanding family of neurotrophic factors (including
brain-derived neurotrophic factor and the neurotrophins) that control the development and survival
of certain neuronal populations both in the peripheral and in the central nervous systems. Its
biological effects are mediated by a high-affinity ligand-receptor interaction and a tyrosine kinase
signalling pathway. A potential use for NGF and its relatives in the treatment of neurological
disorders such as Alzheimer's disease and Parkinson's disease requires an understanding of the
structure-function relationships of NGF. NGF is a dimeric molecule, with 118 amino acids per
protomer. We report the crystal structure of the murine NGF dimer at 2.3-A resolution, which
reveals a novel protomer structure consisting of three antiparallel pairs of beta strands, together
forming a flat surface. Two subunits associate through this surface, thus burying a total of 2,332
A. Four loop regions, which contain many of the variable residues observed between different
NGF-related molecules, may determine the different receptor specificities. A clustering of
positively charged side chains may provide a complementary interaction with the acidic low-affinity
NGF receptor. The structure provides a model for rational design of analogues of NGF and its
relatives and for testing the NGF-receptor recognition determinants critical for signal
transduction. 

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