 |
PDBsum entry 1hcf
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Transferase/hormone
|
PDB id
|
|
|
|
1hcf
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
Contents |
 |
|
|
|
|
|
|
|
|
|
|
|
121 a.a.
|
|
|
|
|
|
|
|
|
|
|
121 a.a.
|
|
|
|
|
|
|
|
|
|
|
101 a.a.
|
|
|
|
|
|
|
|
|
|
|
* Residue conservation analysis
|
|
|
|
|
References listed in PDB file
|
|
|
Key reference
|
|
|
Title
|
|
Specificity in trk receptor:neurotrophin interactions: the crystal structure of trkb-D5 in complex with neurotrophin-4/5.
|
|
|
Authors
|
|
M.J.Banfield,
R.L.Naylor,
A.G.Robertson,
S.J.Allen,
D.Dawbarn,
R.L.Brady.
|
|
|
Ref.
|
|
Structure, 2001,
9,
1191-1199.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
Abstract
|
|
|
BACKGROUND: The binding of neurotrophin ligands to their respective Trk cellular
receptors initiates intracellular signals essential for the growth and survival
of neurons. The site of neurotrophin binding has been located to the fifth
extracellular domain of the Trk receptor, with this region regulating both the
affinity and specificity of Trk receptor:neurotrophin interaction. Neurotrophin
function has been implicated in a number of neurological disorders, including
Alzheimer's disease and Parkinson's disease. RESULTS: We have determined the 2.7
A crystal structure of neurotrophin-4/5 bound to the neurotrophin binding domain
of its high-affinity receptor TrkB (TrkB-d5). As previously seen in the
interaction of nerve growth factor with TrkA, neurotrophin-4/5 forms a crosslink
between two spatially distant receptor molecules. The contacts formed in the
TrkB-d5:neurotrophin-4/5 complex can be divided into a conserved area similar to
a region observed in the TrkA-d5:NGF complex and a second site-unique in each
ligand-receptor pair-formed primarily by the ordering of the neurotrophin N
terminus. CONCLUSIONS: Together, the structures of the TrkB-d5:NT-4/5 and
TrkA-d5:NGF complexes confirm a consistent pattern of recognition in Trk
receptor:neurotrophin complex formation. In both cases, the N terminus of the
neurotrophin becomes ordered only on complex formation. This ordering appears to
be directed largely by the receptor surface, with the resulting complementary
surfaces providing the main determinant of receptor specificity. These features
provide an explanation both for the limited crossreactivity observed between the
range of neurotrophins and Trk receptors and for the high-affinity binding
associated with respective ligand-receptor pairs.
|
|
|
|
|
|
Figure 3.
Figure 3. Contacts Formed in the TrkB-d5:NT-4/5
ComplexContacts formed at (a) the conserved patch and (b) the
specificity patch.Stereo views showing fragments of the TrkB-d5
Ca trace in cyan and those of the NT-4/5 Ca trace in red and
blue. Secondary structure features and relevant amino acids are
labeled. In (b), TrkB-d5 strands shown are ABED from bottom to
top. Bonds in individual residues are shown in khaki for TrkB
and light gray for NT-4/5. Intermolecular hydrogen bonds are
displayed as dashed lines.
|
|
|
|
|
|
The above figure is
reprinted
by permission from Cell Press:
Structure
(2001,
9,
1191-1199)
copyright 2001.
|
|
|
Secondary reference #1
|
|
|
Title
|
|
Identification and structure of the nerve growth factor binding site on trka.
|
|
|
Authors
|
|
A.G.Robertson,
M.J.Banfield,
S.J.Allen,
J.A.Dando,
G.G.Mason,
S.J.Tyler,
G.S.Bennett,
S.D.Brain,
A.R.Clarke,
R.L.Naylor,
G.K.Wilcock,
R.L.Brady,
D.Dawbarn.
|
|
|
Ref.
|
|
Biochem Biophys Res Commun, 2001,
282,
131-141.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
|
|
|
Secondary reference #2
|
|
|
Title
|
|
Crystal structure of nerve growth factor in complex with the ligand-Binding domain of the trka receptor.
|
|
|
Authors
|
|
C.Wiesmann,
M.H.Ultsch,
S.H.Bass,
A.M.De vos.
|
|
|
Ref.
|
|
Nature, 1999,
401,
184-188.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Figure 1.
Figure 1 Overall structure of the complex. a, b, Two
orientations related by a rotation of 90° about the horizontal
axis. The NGF monomers are red and blue; TrkA-d5 is green. The
termini, some relevant loops and the secondary structure
elements are labelled. In a, loops L2 and L4 of NGF and the
C-terminus of TrkA-d5 (residue 382) point towards the membrane.
|
|
Figure 3.
Figure 3 The interface between NGF and TrkA-d5. a, The
binding epitopes of NGF to its receptors TrkA and p75. NGF is
shown as a space-filling model, and TrkA-d5 in ribbon rendering.
The NGF residues in the interface with TrkA-d5 are colour-coded
in different shades of red, reflecting the percentage of
accessible surface buried in the interface (dark red, 75-100%;
orange, 50-75%; light orange, 25-50%; yellow, 0-25%). The
conserved and specificity patches in the interface are outlined
(circles: the two symmetrical specificity patches; ovals: the
two symmetrical common patches), and Arg 103 (in red) on each
NGF monomer is labelled. Loops L2 and L4, which are proposed to
interact with the linker between TrkA-d5 and the membrane, are
dark green. Residues important for binding to p75 (refs 12, 23)
are blue. b, Stereo view showing the environment of Arg 103 of
NGF in the conserved portion of the interface. c, Stereo view
showing interactions between the N terminus of NGF and the
specificity patch of TrkA-d5.
|
|
|
|
|
|
The above figures are
reproduced from the cited reference
with permission from Macmillan Publishers Ltd
|
|
|
Secondary reference #3
|
|
|
Title
|
|
Crystal structures of the neurotrophin-Binding domain of trka, Trkb and trkc.
|
|
|
Authors
|
|
M.H.Ultsch,
C.Wiesmann,
L.C.Simmons,
J.Henrich,
M.Yang,
D.Reilly,
S.H.Bass,
A.M.De vos.
|
|
|
Ref.
|
|
J Mol Biol, 1999,
290,
149-159.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Figure 2.
Figure 2. The relationship between the artifactual
dimers and the modeled monomers. One monomer is
colored red, the other green, and the hinge segment is
shown in yellow. The residue whose position is affected
by the remodeling is shown as a green or red dot.
(a) Topology diagram of the ABED sheet observed in
the crystal structures. (b) Topology of the ABED sheet
after remodeling the AB loop.
|
|
Figure 3.
Figure 3. Models of the ligand-
binding domain of the Trk recep-
tors compared to the structure of
telokin. The b-strands are shown as
green arrows and labeled in TrkA-
d5 and telokin, a helical segment is
depicted as a red ribbon, and loops
are colored yellow and labeled in
TrkB-d5 and TrkC-d5. The exposed
disulfide bridge connecting strands
B and E in the Trk receptors is
shown in ball-and-stick rendering.
(a) TrkA-d5; (b) TrkB-d5; (c) TrkC-
d5; (d) telokin, with the cysteine
residues that usually (but not in tel-
okin) form a buried disulfide bond
shown in ball-and-stick rendering.
|
|
|
|
|
|
The above figures are
reproduced from the cited reference
with permission from Elsevier
|
|
|
Secondary reference #4
|
|
|
Title
|
|
The structures of the neurotrophin 4 homodimer and the brain-Derived neurotrophic factor/neurotrophin 4 heterodimer reveal a common trk-Binding site.
|
|
|
Authors
|
|
R.C.Robinson,
C.Radziejewski,
G.Spraggon,
J.Greenwald,
M.R.Kostura,
L.D.Burtnick,
D.I.Stuart,
S.Choe,
E.Y.Jones.
|
|
|
Ref.
|
|
Protein Sci, 1999,
8,
2589-2597.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
|
|
|
|
|
|
|
