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PDBsum entry 1hcf
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protein ligands Protein-protein interface(s) links
Transferase/hormone PDB id
1hcf

 

 

 

 

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Contents
Protein chains
121 a.a. *
121 a.a. *
101 a.a. *
Ligands
SO4 ×4
Waters ×60
* Residue conservation analysis
PDB id:
1hcf
Name: Transferase/hormone
Title: Crystal structure of trkb-d5 bound to neurotrophin-4/5
Structure: Neurotrophin-4. Chain: a, b. Fragment: active, fragment. Pro-region cleaved. Synonym: neurotrophin-5, neurotrophin-4/5, nt-4/5. Bdnf/nt-3 growth factors receptor. Chain: x, y. Fragment: extracellular domain 5 (residues 286 - 383). Synonym: trkb, gp145-trkb. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Cellular_location: extracellular. Cellular_location: plasma membrane. Expressed in: escherichia coli. Expression_system_taxid: 511693.
Biol. unit: Tetramer (from PDB file)
Resolution:
2.70Å     R-factor:   0.218     R-free:   0.264
Authors: M.J.Banfield,R.L.Naylor,A.G.S.Robertson,S.J.Allen,D.Dawbarn,R.L.Brady
Key ref:
M.J.Banfield et al. (2001). Specificity in Trk receptor:neurotrophin interactions: the crystal structure of TrkB-d5 in complex with neurotrophin-4/5. Structure, 9, 1191-1199. PubMed id: 11738045 DOI: 10.1016/S0969-2126(01)00681-5
Date:
03-May-01     Release date:   06-Dec-01    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
P34130  (NTF4_HUMAN) -  Neurotrophin-4 from Homo sapiens
Seq:
Struc: 		210 a.a.
121 a.a.
Protein chain
P34130  (NTF4_HUMAN) -  Neurotrophin-4 from Homo sapiens
Seq:
Struc: 		210 a.a.
121 a.a.
Protein chains
Q16620  (NTRK2_HUMAN) -  BDNF/NT-3 growth factors receptor from Homo sapiens
Seq:
Struc: 		 
Seq:
Struc: 		822 a.a.
101 a.a.*
Key:    Secondary structure  CATH domain
* PDB and UniProt seqs differ at 2 residue positions (black crosses)

 Enzyme reactions 
   Enzyme class: Chains X, Y: E.C.2.7.10.1  - receptor protein-tyrosine kinase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H+
L-tyrosyl-[protein]
 + ATP
 = O-phospho-L-tyrosyl-[protein]
 + ADP
 + H(+)
Molecule diagrams generated from .mol files obtained from the KEGG ftp site

 

 
    Added reference    
 
 
DOI no: 10.1016/S0969-2126(01)00681-5 Structure 9:1191-1199 (2001)
PubMed id: 11738045  
 
 
Specificity in Trk receptor:neurotrophin interactions: the crystal structure of TrkB-d5 in complex with neurotrophin-4/5.
M.J.Banfield, R.L.Naylor, A.G.Robertson, S.J.Allen, D.Dawbarn, R.L.Brady.
 
  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.
 
  Selected figure(s)  
 
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.  
  Figure was selected by the author.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21039416 M.Cazorla, J.Arrang, and J.Prémont (2011).
Pharmacological characterization of six trkB antibodies reveals a novel class of functional agents for the study of the BDNF receptor.
  Br J Pharmacol, 162, 947-960.  
21505263 M.Cazorla, J.Prémont, A.Mann, N.Girard, C.Kellendonk, and D.Rognan (2011).
Identification of a low-molecular weight TrkB antagonist with anxiolytic and antidepressant activity in mice.
  J Clin Invest, 121, 1846-1857.  
21419569 R.Ho, J.E.Minturn, A.M.Simpson, R.Iyer, J.E.Light, A.E.Evans, and G.M.Brodeur (2011).
The effect of P75 on Trk receptors in neuroblastomas.
  Cancer Lett, 305, 76-85.  
20360537 B.Cristofaro, O.A.Stone, A.Caporali, D.Dawbarn, N.Ieronimakis, M.Reyes, P.Madeddu, D.O.Bates, and C.Emanueli (2010).
Neurotrophin-3 is a novel angiogenic factor capable of therapeutic neovascularization in a mouse model of limb ischemia.
  Arterioscler Thromb Vasc Biol, 30, 1143-1150.  
  20806036 E.N.Vithana, M.E.Nongpiur, D.Venkataraman, S.H.Chan, J.Mavinahalli, and T.Aung (2010).
Identification of a novel mutation in the NTF4 gene that causes primary open-angle glaucoma in a Chinese population.
  Mol Vis, 16, 1640-1645.  
  20653959 J.E.Biggs, V.B.Lu, M.J.Stebbing, S.Balasubramanyan, and P.A.Smith (2010).
Is BDNF sufficient for information transfer between microglia and dorsal horn neurons during the onset of central sensitization?
  Mol Pain, 6, 44.  
19765683 F.Pasutto, T.Matsumoto, C.Y.Mardin, H.Sticht, J.H.Brandstätter, K.Michels-Rautenstrauss, N.Weisschuh, E.Gramer, W.D.Ramdas, L.M.van Koolwijk, C.C.Klaver, J.R.Vingerling, B.H.Weber, F.E.Kruse, B.Rautenstrauss, Y.A.Barde, and A.Reis (2009).
Heterozygous NTF4 mutations impairing neurotrophin-4 signaling in patients with primary open-angle glaucoma.
  Am J Hum Genet, 85, 447-456.  
18998753 J.J.Watson, S.J.Allen, and D.Dawbarn (2008).
Targeting nerve growth factor in pain: what is the therapeutic potential?
  BioDrugs, 22, 349-359.  
17439940 L.Ivanisevic, W.Zheng, S.B.Woo, K.E.Neet, and H.U.Saragovi (2007).
TrkA receptor "hot spots" for binding of NT-3 as a heterologous ligand.
  J Biol Chem, 282, 16754-16763.  
16798810 M.Berrera, A.Cattaneo, and P.Carloni (2006).
Molecular simulation of the binding of nerve growth factor peptide mimics to the receptor tyrosine kinase A.
  Biophys J, 91, 2063-2071.  
15572360 G.Williams, E.J.Williams, P.Maison, M.N.Pangalos, F.S.Walsh, and P.Doherty (2005).
Overcoming the inhibitors of myelin with a novel neurotrophin strategy.
  J Biol Chem, 280, 5862-5869.  
15094157 A.Bennasroune, A.Gardin, D.Aunis, G.Crémel, and P.Hubert (2004).
Tyrosine kinase receptors as attractive targets of cancer therapy.
  Crit Rev Oncol Hematol, 50, 23-38.  
15260984 L.F.Reichardt, and W.C.Mobley (2004).
Going the distance, or not, with neurotrophin signals.
  Cell, 118, 141-143.  
12676795 E.J.Huang, and L.F.Reichardt (2003).
Trk receptors: roles in neuronal signal transduction.
  Annu Rev Biochem, 72, 609-642.  
12730196 P.D.O'Leary, and R.A.Hughes (2003).
Design of potent peptide mimetics of brain-derived neurotrophic factor.
  J Biol Chem, 278, 25738-25744.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time.

 

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