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PDBsum entry 1sg1
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protein metals Protein-protein interface(s) links
Hormone/growth factor/membrane protein PDB id
1sg1

 

 

 

 

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Contents
Protein chains
99 a.a. *
160 a.a. *
Metals
_CL
Waters ×375
* Residue conservation analysis
PDB id:
1sg1
Name: Hormone/growth factor/membrane protein
Title: Crystal structure of the receptor-ligand complex between nerve growth factor and the common neurotrophin receptor p75
Structure: Beta-nerve growth factor. Chain: a, b. Synonym: beta-ngf. Engineered: yes. Tumor necrosis factor receptor superfamily member 16. Chain: x. Synonym: low- affinity nerve growth factor receptor, ngf receptor, gp80-lngfr, p75 icd, low affinity neurotrophin receptor p75ntr. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: ngfb. Expressed in: escherichia coli. Expression_system_taxid: 562. Rattus norvegicus. Norway rat. Organism_taxid: 10116.
Biol. unit: Trimer (from PQS)
Resolution:
2.40Å     R-factor:   0.243     R-free:   0.269
Authors: X.L.He,K.C.Garcia
Key ref:
X.L.He and K.C.Garcia (2004). Structure of nerve growth factor complexed with the shared neurotrophin receptor p75. Science, 304, 870-875. PubMed id: 15131306 DOI: 10.1126/science.1095190
Date:
22-Feb-04     Release date:   01-Jun-04    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P01138  (NGF_HUMAN) -  Beta-nerve growth factor from Homo sapiens
Seq:
Struc: 		241 a.a.
99 a.a.
Protein chain
Pfam   ArchSchema ?
P07174  (TNR16_RAT) -  Tumor necrosis factor receptor superfamily member 16 from Rattus norvegicus
Seq:
Struc: 		425 a.a.
160 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 

 
DOI no: 10.1126/science.1095190 Science 304:870-875 (2004)
PubMed id: 15131306  
 
 
Structure of nerve growth factor complexed with the shared neurotrophin receptor p75.
X.L.He, K.C.Garcia.
 
  ABSTRACT  
 
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.
 
  Selected figure(s)  
 
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. 		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".
 
  The above figures are reprinted by permission from the AAAs: Science (2004, 304, 870-875) copyright 2004.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
20170684 G.Niewiadomska, A.Mietelska-Porowska, and M.Mazurkiewicz (2011).
The cholinergic system, nerve growth factor and the cytoskeleton.
  Behav Brain Res, 221, 515-526.  
21337622 S.Y.Ponomarev, and J.Audie (2011).
Computational prediction and analysis of the DR6-NAPP interaction.
  Proteins, 79, 1376-1395.  
20047901 A.L.Scott, and M.S.Ramer (2010).
Schwann cell p75NTR prevents spontaneous sensory reinnervation of the adult spinal cord.
  Brain, 133, 421-432.  
  20186714 K.G.Bath, and F.S.Lee (2010).
Neurotrophic factor control of adult SVZ neurogenesis.
  Dev Neurobiol, 70, 339-349.  
  20186707 K.K.Teng, S.Felice, T.Kim, and B.L.Hempstead (2010).
Understanding proneurotrophin actions: Recent advances and challenges.
  Dev Neurobiol, 70, 350-359.  
20333308 M.Cazorla, A.Jouvenceau, C.Rose, J.P.Guilloux, C.Pilon, A.Dranovsky, and J.Prémont (2010).
Cyclotraxin-B, the first highly potent and selective TrkB inhibitor, has anxiolytic properties in mice.
  PLoS One, 5, e9777.  
  19126759 A.Caporali, and C.Emanueli (2009).
Cardiovascular actions of neurotrophins.
  Physiol Rev, 89, 279-308.  
  19526280 B.L.Hempstead (2009).
Commentary: Regulating proNGF Action: Multiple Targets for Therapeutic Intervention.
  Neurotox Res, 16, 255-260.  
19217904 E.C.Johnson, Y.Guo, W.O.Cepurna, and J.C.Morrison (2009).
Neurotrophin roles in retinal ganglion cell survival: lessons from rat glaucoma models.
  Exp Eye Res, 88, 808-815.  
19122660 E.M.Quistgaard, P.Madsen, M.K.Grøftehauge, P.Nissen, C.M.Petersen, and S.S.Thirup (2009).
Ligands bind to Sortilin in the tunnel of a ten-bladed beta-propeller domain.
  Nat Struct Mol Biol, 16, 96-98.
PDB code: 3f6k
19940174 H.Yano, R.Torkin, L.A.Martin, M.V.Chao, and K.K.Teng (2009).
Proneurotrophin-3 is a neuronal apoptotic ligand: evidence for retrograde-directed cell killing.
  J Neurosci, 29, 14790-14802.  
19838198 L.K.Ely, S.Fischer, and K.C.Garcia (2009).
Structural basis of receptor sharing by interleukin 17 cytokines.
  Nat Immunol, 10, 1245-1251.
PDB code: 3jvf
19376068 M.Vilar, I.Charalampopoulos, R.S.Kenchappa, A.Simi, E.Karaca, A.Reversi, S.Choi, M.Bothwell, I.Mingarro, W.J.Friedman, G.Schiavo, P.I.Bastiaens, P.J.Verveer, B.D.Carter, and C.F.Ibáñez (2009).
Activation of the p75 neurotrophin receptor through conformational rearrangement of disulphide-linked receptor dimers.
  Neuron, 62, 72-83.  
19376060 P.A.Barker (2009).
A p75(NTR) pivoting paradigm propels perspicacity.
  Neuron, 62, 3-5.  
  18678937 A.Hoffmann, P.Neumann, A.Schierhorn, and M.T.Stubbs (2008).
Crystallization of Spätzle, a cystine-knot protein involved in embryonic development and innate immunity in Drosophila melanogaster.
  Acta Crystallogr Sect F Struct Biol Cryst Commun, 64, 707-710.  
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.  
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.  
17313996 L.Puglielli (2008).
Aging of the brain, neurotrophin signaling, and Alzheimer's disease: is IGF1-R the common culprit?
  Neurobiol Aging, 29, 795-811.  
17915332 V.Freund-Michel, and N.Frossard (2008).
The nerve growth factor and its receptors in airway inflammatory diseases.
  Pharmacol Ther, 117, 52-76.  
18596692 Y.Gong, P.Cao, H.J.Yu, and T.Jiang (2008).
Crystal structure of the neurotrophin-3 and p75NTR symmetrical complex.
  Nature, 454, 789-793.
PDB code: 3buk
17928338 C.Tuffereau, K.Schmidt, C.Langevin, F.Lafay, G.Dechant, and M.Koltzenburg (2007).
The rabies virus glycoprotein receptor p75NTR is not essential for rabies virus infection.
  J Virol, 81, 13622-13630.  
17242381 M.Kliemannel, R.Golbik, R.Rudolph, E.Schwarz, and H.Lilie (2007).
The pro-peptide of proNGF: structure formation and intramolecular association with NGF.
  Protein Sci, 16, 411-419.  
17362201 N.J.Gay, and M.Gangloff (2007).
Structure and function of Toll receptors and their ligands.
  Annu Rev Biochem, 76, 141-165.  
17196523 P.A.Barker (2007).
High affinity not in the vicinity?
  Neuron, 53, 1-4.  
17196528 T.Wehrman, X.He, B.Raab, A.Dukipatti, H.Blau, and K.C.Garcia (2007).
Structural and mechanistic insights into nerve growth factor interactions with the TrkA and p75 receptors.
  Neuron, 53, 25-38.
PDB code: 2ifg
16807107 A.Kinkade, and C.F.Ware (2006).
The DARC conspiracy--virus invasion tactics.
  Trends Immunol, 27, 362-367.  
16893414 E.J.Coulson (2006).
Does the p75 neurotrophin receptor mediate Abeta-induced toxicity in Alzheimer's disease?
  J Neurochem, 98, 654-660.  
16939974 L.F.Reichardt (2006).
Neurotrophin-regulated signalling pathways.
  Philos Trans R Soc Lond B Biol Sci, 361, 1545-1564.  
17145551 M.Pehar, M.R.Vargas, K.M.Robinson, P.Cassina, P.England, J.S.Beckman, P.M.Alzari, and L.Barbeito (2006).
Peroxynitrite transforms nerve growth factor into an apoptotic factor for motor neurons.
  Free Radic Biol Med, 41, 1632-1644.  
16917510 N.J.Gay, M.Gangloff, and A.N.Weber (2006).
Toll-like receptors as molecular switches.
  Nat Rev Immunol, 6, 693-698.  
16944323 S.Capsoni, and A.Cattaneo (2006).
On the molecular basis linking Nerve Growth Factor (NGF) to Alzheimer's disease.
  Cell Mol Neurobiol, 26, 619-633.  
16580596 Z.G.Gao, and K.A.Jacobson (2006).
Keynote review: allosterism in membrane receptors.
  Drug Discov Today, 11, 191-202.  
15721744 A.Nykjaer, T.E.Willnow, and C.M.Petersen (2005).
p75NTR--live or let die.
  Curr Opin Neurobiol, 15, 49-57.  
16009712 J.P.Aurikko, B.T.Ruotolo, J.G.Grossmann, M.C.Moncrieffe, E.Stephens, V.M.Leppänen, C.V.Robinson, M.Saarma, R.A.Bradshaw, and T.L.Blundell (2005).
Characterization of symmetric complexes of nerve growth factor and the ectodomain of the pan-neurotrophin receptor, p75NTR.
  J Biol Chem, 280, 33453-33460.  
16001231 K.Susen, and A.Blöchl (2005).
Low concentrations of aggregated beta-amyloid induce neurite formation via the neurotrophin receptor p75.
  J Mol Med, 83, 720-735.  
16297524 N.F.Schor (2005).
The p75 neurotrophin receptor in human development and disease.
  Prog Neurobiol, 77, 201-214.  
15924236 U.L.Rahbek, S.Dissing, C.Thomassen, A.J.Hansen, and K.Tritsaris (2005).
Nerve growth factor activates aorta endothelial cells causing PI3K/Akt- and ERK-dependent migration.
  Pflugers Arch, 450, 355-361.  
16287464 Y.C.Tong, and J.T.Cheng (2005).
Changes in bladder nerve-growth factor and p75 genetic expression in streptozotocin-induced diabetic rats.
  BJU Int, 96, 1392-1396.  
15470383 F.C.Bronfman, and M.Fainzilber (2004).
Multi-tasking by the p75 neurotrophin receptor: sortilin things out?
  EMBO Rep, 5, 867-871.  
15157416 P.A.Barker (2004).
p75NTR is positively promiscuous: novel partners and new insights.
  Neuron, 42, 529-533.  
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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