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PDBsum entry 1bnd

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protein ligands Protein-protein interface(s) links
Complex (growth factor/growth factor) PDB id
1bnd
Jmol PyMol
Contents
Protein chains
109 a.a. *
108 a.a. *
Ligands
IPA
Waters ×210
* Residue conservation analysis
PDB id:
1bnd
Name: Complex (growth factor/growth factor)
Title: Structure of the brain-derived neurotrophic factor(slash)neu 3 heterodimer
Structure: Brain derived neurotrophic factor. Chain: a. Synonym: bdnf. Engineered: yes. Neurotrophin 3. Chain: b. Synonym: nt3. Engineered: yes. Other_details: heterodimer
Source: Homo sapiens. Human. Organism_taxid: 9606. Organ: brain. Expressed in: escherichia coli. Expression_system_taxid: 562. Other_details: supplied by regeneron pharm..
Biol. unit: Tetramer (from PQS)
Resolution:
2.30Å     R-factor:   0.182    
Authors: R.C.Robinson,C.Radziejewski,D.I.Stuart,E.Y.Jones
Key ref:
R.C.Robinson et al. (1995). Structure of the brain-derived neurotrophic factor/neurotrophin 3 heterodimer. Biochemistry, 34, 4139-4146. PubMed id: 7703225 DOI: 10.1021/bi00013a001
Date:
12-Dec-94     Release date:   04-Apr-96    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P23560  (BDNF_HUMAN) -  Brain-derived neurotrophic factor
Seq:
Struc:
247 a.a.
109 a.a.*
Protein chain
Pfam   ArchSchema ?
P20783  (NTF3_HUMAN) -  Neurotrophin-3
Seq:
Struc:
257 a.a.
108 a.a.*
Key:    PfamA domain  PfamB domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 3 residue positions (black crosses)

 Gene Ontology (GO) functional annotation 
  GO annot!
  Biochemical function     receptor binding     2 terms  

 

 
DOI no: 10.1021/bi00013a001 Biochemistry 34:4139-4146 (1995)
PubMed id: 7703225  
 
 
Structure of the brain-derived neurotrophic factor/neurotrophin 3 heterodimer.
R.C.Robinson, C.Radziejewski, D.I.Stuart, E.Y.Jones.
 
  ABSTRACT  
 
The development and sustenance of specific neuronal populations in the peripheral and central nervous systems are controlled through the binding of neurotrophic factors to high-affinity cell surface receptors. The neurotrophins (nerve growth factor, NGF; brain-derived neurotrophic factor, BDNF; neurotrophin 3, NT3; and neurotrophin 4, NT4) are dimeric molecules which share approximately 50% sequence identity. The crystal structure of the murine NGF homodimer [McDonald et al. (1991) Nature 354, 411-414] indicated that the dimer interface corresponds to regions of high sequence conservation throughout the neurotrophin family. This potential compatibility was duly exploited for the production in vitro of noncovalent heterodimers between the different neurotrophins [Radziejewski, C., & Robinson, R.C. (1993) Biochemistry 32, 13350-13356; Jungbluth et al. (1994) Eur. J. Biochem. 221, 677-685]. Here, we report the X-ray structure at 2.3 A resolution of one such heterodimer, between human BDNF, and human NT3. The NGF, BDNF, and NT3 protomers share the same topology and are structurally equivalent in regions which contribute to the dimer interface in line with the propensity of the neurotrophins to form heterodimers. Analysis of the structure of regions of the BDNF/NT3 heterodimer involved in receptor specificity led us to conclude that heterodimer binding to p75 involves distant binding sites separately located on each protomer of the heterodimer. In contrast, heterodimer interactions with the trk receptors probably utilize hybrid binding sites comprised of residues contributed by both protomers in the heterodimer. The existence of such hybrid binding sites for the trk receptor provides an explanation for the lower activity of the BDNF/NT3 heterodimer in comparison to the homodimers.(ABSTRACT TRUNCATED AT 250 WORDS)
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
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.  
20407211 S.M.Massa, T.Yang, Y.Xie, J.Shi, M.Bilgen, J.N.Joyce, D.Nehama, J.Rajadas, and F.M.Longo (2010).
Small molecule BDNF mimetics activate TrkB signaling and prevent neuronal degeneration in rodents.
  J Clin Invest, 120, 1774-1785.  
20524922 Y.Prakash, M.A.Thompson, L.Meuchel, C.M.Pabelick, C.B.Mantilla, S.Zaidi, and R.J.Martin (2010).
Neurotrophins in lung health and disease.
  Expert Rev Respir Med, 4, 395-411.  
  19126759 A.Caporali, and C.Emanueli (2009).
Cardiovascular actions of neurotrophins.
  Physiol Rev, 89, 279-308.  
19674479 H.Koshimizu, K.Kiyosue, T.Hara, S.Hazama, S.Suzuki, K.Uegaki, G.Nagappan, E.Zaitsev, T.Hirokawa, Y.Tatsu, A.Ogura, B.Lu, and M.Kojima (2009).
Multiple functions of precursor BDNF to CNS neurons: negative regulation of neurite growth, spine formation and cell survival.
  Mol Brain, 2, 27.  
19048635 R.G.Soderquist, E.D.Milligan, E.M.Sloane, J.A.Harrison, K.K.Douvas, J.M.Potter, T.S.Hughes, R.A.Chavez, K.Johnson, L.R.Watkins, and M.J.Mahoney (2009).
PEGylation of brain-derived neurotrophic factor for preserved biological activity and enhanced spinal cord distribution.
  J Biomed Mater Res A, 91, 719-729.  
19208630 V.Veverka, A.J.Henry, P.M.Slocombe, A.Ventom, B.Mulloy, F.W.Muskett, M.Muzylak, K.Greenslade, A.Moore, L.Zhang, J.Gong, X.Qian, C.Paszty, R.J.Taylor, M.K.Robinson, and M.D.Carr (2009).
Characterization of the Structural Features and Interactions of Sclerostin: MOLECULAR INSIGHT INTO A KEY REGULATOR OF Wnt-MEDIATED BONE FORMATION.
  J Biol Chem, 284, 10890-10900.
PDB code: 2k8p
18809686 J.M.Fletcher, C.J.Morton, R.A.Zwar, S.S.Murray, P.D.O'Leary, and R.A.Hughes (2008).
Design of a Conformationally Defined and Proteolytically Stable Circular Mimetic of Brain-derived Neurotrophic Factor.
  J Biol Chem, 283, 33375-33383.  
18347020 M.Gangloff, A.Murali, J.Xiong, C.J.Arnot, A.N.Weber, A.M.Sandercock, C.V.Robinson, R.Sarisky, A.Holzenburg, C.Kao, and N.J.Gay (2008).
Structural insight into the mechanism of activation of the Toll receptor by the dimeric ligand Spätzle.
  J Biol Chem, 283, 14629-14635.  
16939974 L.F.Reichardt (2006).
Neurotrophin-regulated signalling pathways.
  Philos Trans R Soc Lond B Biol Sci, 361, 1545-1564.  
15664176 H.Lou, S.K.Kim, E.Zaitsev, C.R.Snell, B.Lu, and Y.P.Loh (2005).
Sorting and activity-dependent secretion of BDNF require interaction of a specific motif with the sorting receptor carboxypeptidase e.
  Neuron, 45, 245-255.  
11842409 T.Li, J.Talvenheimo, L.Zeni, R.Rosenfeld, G.Stearns, and T.Arakawa (2002).
Changes in protein conformation and dynamics upon complex formation of brain-derived neurotrophic factor and its receptor: investigation by isotope-edited Fourier transform IR spectroscopy.
  Biopolymers, 67, 10-19.  
11520916 E.J.Huang, and L.F.Reichardt (2001).
Neurotrophins: roles in neuronal development and function.
  Annu Rev Neurosci, 24, 677-736.  
11040419 M.G.Murer, Q.Yan, and R.Raisman-Vozari (2001).
Brain-derived neurotrophic factor in the control human brain, and in Alzheimer's disease and Parkinson's disease.
  Prog Neurobiol, 63, 71.  
11520933 M.V.Sofroniew, C.L.Howe, and W.C.Mobley (2001).
Nerve growth factor signaling, neuroprotection, and neural repair.
  Annu Rev Neurosci, 24, 1217-1281.  
  10595525 I.L.Shamovsky, G.M.Ross, R.J.Riopelle, and D.F.Weaver (1999).
The interaction of neurotrophins with the p75NTR common neurotrophin receptor: a comprehensive molecular modeling study.
  Protein Sci, 8, 2223-2233.  
  10595557 L.R.De Young, C.H.Schmelzer, and L.E.Burton (1999).
A common mechanism for recombinant human NGF, BDNF, NT-3, and murine NGF slow unfolding.
  Protein Sci, 8, 2513-2518.  
  10631974 R.C.Robinson, C.Radziejewski, G.Spraggon, J.Greenwald, M.R.Kostura, L.D.Burtnick, D.I.Stuart, S.Choe, and E.Y.Jones (1999).
The structures of the neurotrophin 4 homodimer and the brain-derived neurotrophic factor/neurotrophin 4 heterodimer reveal a common Trk-binding site.
  Protein Sci, 8, 2589-2597.
PDB codes: 1b8k 1b8m 1b98
9786342 C.F.Ibáñez (1998).
Emerging themes in structural biology of neurotrophic factors.
  Trends Neurosci, 21, 438-444.  
9697410 K.Mizuguchi, J.S.Parker, T.L.Blundell, and N.J.Gay (1998).
Getting knotted: a model for the structure and activation of Spätzle.
  Trends Biochem Sci, 23, 239-242.  
9726969 N.Beglova, L.LeSauteur, I.Ekiel, H.U.Saragovi, and K.Gehring (1998).
Solution structure and internal motion of a bioactive peptide derived from nerve growth factor.
  J Biol Chem, 273, 23652-23658.  
  9568907 S.B.Woo, C.Whalen, and K.E.Neet (1998).
Characterization of the recombinant extracellular domain of the neurotrophin receptor TrkA and its interaction with nerve growth factor (NGF).
  Protein Sci, 7, 1006-1016.  
9566117 C.McInnes, and B.D.Sykes (1997).
Growth factor receptors: structure, mechanism, and drug discovery.
  Biopolymers, 43, 339-366.  
9256278 G.M.Ross, I.L.Shamovsky, G.Lawrance, M.Solc, S.M.Dostaler, S.L.Jimmo, D.F.Weaver, and R.J.Riopelle (1997).
Zinc alters conformation and inhibits biological activities of nerve growth factor and related neurotrophins.
  Nat Med, 3, 872-878.  
9364335 K.Kullander, A.Kylberg, and T.Ebendal (1997).
Specificity of neurotrophin-3 determined by loss-of-function mutagenesis.
  J Neurosci Res, 50, 496-503.  
8887120 A.M.Jackson, T.Klonisch, A.J.Lapthorn, P.Berger, N.W.Isaacs, P.J.Delves, T.Lund, and I.M.Roitt (1996).
Identification and selective destruction of shared epitopes in human chorionic gonadotropin beta subunit.
  J Reprod Immunol, 31, 21-36.  
  8844846 L.R.De Young, L.E.Burton, J.Liu, M.F.Powell, C.H.Schmelzer, and N.J.Skelton (1996).
RhNGF slow unfolding is not due to proline isomerization: possibility of a cystine knot loop-threading mechanism.
  Protein Sci, 5, 1554-1566.  
8621424 M.Rydén, and C.F.Ibáñez (1996).
Binding of neurotrophin-3 to p75LNGFR, TrkA, and TrkB mediated by a single functional epitope distinct from that recognized by trkC.
  J Biol Chem, 271, 5623-5627.  
8911742 R.A.Hughes, and P.D.O'Leary (1996).
Neurotrophic factors and the development of drugs to promote motoneuron survival.
  Clin Exp Pharmacol Physiol, 23, 965-969.  
  8732770 R.C.Robinson, C.Radziejewski, D.I.Stuart, and E.Y.Jones (1996).
Crystals of the neurotrophins.
  Protein Sci, 5, 973-977.  
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. Where a reference describes a PDB structure, the PDB code is shown on the right.

 

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