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PDBsum entry 1sg1
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Hormone/growth factor/membrane protein
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PDB id
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1sg1
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Contents |
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* Residue conservation analysis
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References listed in PDB file
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Key reference
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Title
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Structure of nerve growth factor complexed with the shared neurotrophin receptor p75.
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Authors
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X.L.He,
K.C.Garcia.
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Ref.
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Science, 2004,
304,
870-875.
[DOI no: ]
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PubMed id
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Abstract
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Neurotrophins are secreted growth factors critical for the development and
maintenance of the vertebrate nervous system. Neurotrophins activate two types
of cell surface receptors, the Trk receptor tyrosine kinases and the shared p75
neurotrophin receptor. We have determined the 2.4 A crystal structure of the
prototypic neurotrophin, nerve growth factor (NGF), complexed with the
extracellular domain of p75. Surprisingly, the complex is composed of an NGF
homodimer asymmetrically bound to a single p75. p75 binds along the homodimeric
interface of NGF, which disables NGF's symmetry-related second p75 binding site
through an allosteric conformational change. Thus, neurotrophin signaling
through p75 may occur by disassembly of p75 dimers and assembly of asymmetric
2:1 neurotrophin/p75 complexes, which could potentially engage a Trk receptor to
form a trimolecular signaling complex.
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Figure 1.
Fig. 1. Structure of NGF complexed with p75. (A) p75 binds
along one side of the NGF homodimer. Backbone representation of
NGF monomer A is colored green; monomer B, blue; and p75,
purple. Disulfide bonds are shown as green sticks. Other figures
have the same coloring scheme. (B) p75 binds across the NGF
dimerization interface. Front view, with a horizontal rotation
of 90° from the orientation of the complex seen in (A) with
NGF depicted as surface and p75 as tube. (C) p75 uses the
opposite side as TNFR-SF members for ligand binding, but both
bind within their ligands' oligomer interfaces. One copy of
TNF-R1 from the TNF-ß-TNF-R1 complex (16) is superimposed
with p75 from the NGF-p75 complex. The two receptors used in
superimposition are depicted in main-chain traces, and the other
molecules in space-filling format.
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Figure 2.
Fig. 2. The interaction between NGF and p75. (A) Close-up of
the site I interface (NGF monomer A is green; monomer B, blue;
and p75, purple). The backbone is depicted as tubes, and side
chains are depicted as sticks. The buried salt bridge between
NGF Lys88A and p75 Asp41 in site I is highlighted by thickened
side chains. (B) Close-up of the site II interface. (C) Charge
complementarity between the acidic p75 and the basic NGF dimer
is shown as their respective GRASP surfaces. Acidic is red and
basic is blue. (D) A representative electron density map (  A
2F[obs] - F[calc]) around the patch 1 of site I, showing the
knob-in-hole surface complementarity. (E) NT sequence alignment
showing that the p75 contact residues are conserved across all
NTs. Monomer A residues are shaded in green and monomer B
residues shaded in blue. Site I residues are labeled "1," and
site II residues are labeled "2".
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The above figures are
reprinted
by permission from the AAAs:
Science
(2004,
304,
870-875)
copyright 2004.
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