Database accession: MF2110010
Name: Nerve growth factor (NGF)
PDB ID: 1bet
Experimental method: X-ray (2.30 Å)
Assembly: homodimer
Source organism: Mus musculus
Primer publication of the structure:
McDonald NQ, Lapatto R, Murray-Rust J, Gunning J, Wlodawer A, Blundell TL
New protein fold revealed by a 2.3-A resolution crystal structure of nerve growth factor.
(1991) Nature 354: 411-4
PMID: 1956407
Abstract:
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.
Annotations from the GeneOntology database. Only terms that fit at least two of the interacting proteins are shown. Molecular function:
growth factor activity The function that stimulates a cell to grow or proliferate. Most growth factors have other actions besides the induction of cell growth or proliferation.
metalloendopeptidase inhibitor activity Stops, prevents or reduces the activity of metalloendopeptidases, enzymes that catalyze the hydrolysis of nonterminal peptide bonds in a polypeptide chain and contain a chelated metal ion at their active sites which is essential to their catalytic activity.
transmembrane receptor protein tyrosine kinase activator activity Binds to and increases the activity of a transmembrane receptor protein tyrosine kinase.
receptor signaling protein activity Conveys a signal from an upstream receptor or intracellular signal transducer, converting the signal into a form where it can ultimately trigger a change in the state or activity of a cell.
nerve growth factor receptor binding Interacting selectively and non-covalently with the nerve growth factor receptor.
Biological process:
neuron apoptotic process Any apoptotic process in a neuron, the basic cellular unit of nervous tissue. Each neuron consists of a body, an axon, and dendrites. Their purpose is to receive, conduct, and transmit impulses in the nervous system.
negative regulation of neuron apoptotic process Any process that stops, prevents, or reduces the frequency, rate or extent of cell death by apoptotic process in neurons.
positive regulation of protein autophosphorylation Any process that activates or increases the frequency, rate or extent of the phosphorylation by a protein of one or more of its own residues.
extrinsic apoptotic signaling pathway in absence of ligand A series of molecular signals in which a signal is conveyed from the cell surface to trigger the apoptotic death of a cell. The pathway starts with withdrawal of a ligand from a cell surface receptor, and ends when the execution phase of apoptosis is triggered.
phosphatidylinositol-mediated signaling A series of molecular signals in which a cell uses a phosphatidylinositol-mediated signaling to convert a signal into a response. Phosphatidylinositols include phosphatidylinositol (PtdIns) and its phosphorylated derivatives.
regulation of release of sequestered calcium ion into cytosol Any process that modulates the frequency, rate or extent of the release into the cytosolic compartment of calcium ions sequestered in the endoplasmic reticulum or mitochondria.
positive regulation of Ras protein signal transduction Any process that activates or increases the frequency, rate or extent of Ras protein signal transduction.
regulation of neurotransmitter secretion Any process that modulates the frequency, rate or extent of the regulated release of a neurotransmitter from a cell.
extrinsic apoptotic signaling pathway via death domain receptors A series of molecular signals in which a signal is conveyed from the cell surface to trigger the apoptotic death of a cell. The pathway starts with a ligand binding to a death domain receptor on the cell surface, and ends when the execution phase of apoptosis is triggered.
negative regulation of endopeptidase activity Any process that decreases the frequency, rate or extent of endopeptidase activity, the endohydrolysis of peptide bonds within proteins.
positive regulation of collateral sprouting Any process that activates or increases the frequency, rate or extent of collateral sprouting.
neuron projection morphogenesis The process in which the anatomical structures of a neuron projection are generated and organized. A neuron projection is any process extending from a neural cell, such as axons or dendrites.
nerve growth factor signaling pathway A series of molecular signals initiated by the binding of nerve growth factor (NGF) to a receptor on the surface of the target cell, and ending with regulation of a downstream cellular process, e.g. transcription.
positive regulation of neuron maturation Any process that activates or increases the frequency, rate or extent of neuron maturation.
positive regulation of protein ubiquitination Any process that activates or increases the frequency, rate or extent of the addition of ubiquitin groups to a protein.
nerve growth factor processing The generation of a mature nerve growth factor (NGF) by proteolysis of a precursor.
positive regulation of axon extension Any process that activates or increases the frequency, rate or extent of axon extension.
circadian rhythm Any biological process in an organism that recurs with a regularity of approximately 24 hours.
activation of transmembrane receptor protein tyrosine kinase activity Any process that initiates the activity of the inactive transmembrane receptor protein tyrosine kinase activity.
positive regulation of apoptotic process Any process that activates or increases the frequency, rate or extent of cell death by apoptotic process.
positive regulation of neurotrophin TRK receptor signaling pathway Any process that activates or increases the frequency, rate or extent of the neurotrophin TRK receptor signaling pathway.
positive regulation of sequence-specific DNA binding transcription factor activity Any process that activates or increases the frequency, rate or extent of activity of a transcription factor, any factor involved in the initiation or regulation of transcription.
Cellular component:
cytoplasmic, membrane-bounded vesicle A membrane-bounded vesicle found in the cytoplasm of the cell.
endoplasmic reticulum lumen The volume enclosed by the membranes of the endoplasmic reticulum.
Structural annotations of the participating protein chains.Entry contents: 2 distinct polypeptide molecules
Chains: A, B
Notes: Chain B was generated from chain A using the biomatrices described in the original PDB file.
Number of unique protein segments: 1
Name: Beta-nerve growth factor
Source organism: Mus musculus
Length: 107 residues
Sequence:Sequence according to PDB SEQRESGEFSVCDSVSVWVGDKTTATDIKGKEVTVLAEVNINNSVFRQYFFETKCRASNPVESGCRGIDSKHWNSYCTTTHTFVKALTTDEKQAAWRFIRIDTACVCVLSRKA
UniProtKB AC: P01139 (positions: 131-237) Coverage: 44.4%
UniRef90 AC: UniRef90_P01139 (positions: 131-237)
Name: Beta-nerve growth factor
Source organism: Mus musculus
Length: 107 residues
Sequence:Sequence according to PDB SEQRESGEFSVCDSVSVWVGDKTTATDIKGKEVTVLAEVNINNSVFRQYFFETKCRASNPVESGCRGIDSKHWNSYCTTTHTFVKALTTDEKQAAWRFIRIDTACVCVLSRKA
UniProtKB AC: P01139 (positions: 131-237) Coverage: 44.4%
UniRef90 AC: UniRef90_P01139 (positions: 131-237)
Evidence demonstrating that the participating proteins are unstructured prior to the interaction and their folding is coupled to binding. Complex evidence:
Various dimeric members of neurotrophic factors (including human/mouse nerve growth factor, human brain-derived neurotrophic factor (BDNF), neurotrophin 3 (NT-3), and neurotrophin 4/5 (NT-4/5)) have been shown to fold and dimerize at the same time via a two-state process (PMID: 8161524). While the members of this family show a significant variance in sequence, they adopt a highly similar structure upon binding and behave almost identically in unfolding/refolding experiments. Thus the two-state folding/binding nature seems to be a hallmark of NGF and closely related proteins.
Structures from the PDB that contain the same number of proteins, and the proteins from the two structures show a sufficient degree of pairwise similarity, i.e. they belong to the same UniRef90 cluster (the full proteins exhibit at least 90% sequence identity) and convey roughly the same region to their respective interactions (the two regions from the two proteins share a minimum of 70% overlap). Download our modified structure (.pdb)
