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PDBsum entry 1ozn
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Signaling protein PDB id
1ozn

 

 

 

 

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Contents
Protein chain
284 a.a. *
Ligands
NAG-NDG-MAN-MAN
NAG-NDG-BMA
ACY ×3
Waters ×354
* Residue conservation analysis
PDB id:
1ozn
Name: Signaling protein
Title: 1.5a crystal structure of the nogo receptor ligand binding domain reveals a convergent recognition scaffold mediating inhibition of myelination
Structure: Reticulon 4 receptor. Chain: a. Fragment: ligand binding domain. Synonym: nogo receptor, ngr, nogo-66 receptor. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: rtn4r or nogor. Expressed in: trichoplusia ni. Expression_system_taxid: 7111.
Resolution:
1.52Å     R-factor:   0.167     R-free:   0.198
Authors: X.He,J.F.Bazan,J.B.Park,G.Mcdermott,Z.He,K.C.Garcia
Key ref:
X.L.He et al. (2003). Structure of the Nogo receptor ectodomain: a recognition module implicated in myelin inhibition. Neuron, 38, 177-185. PubMed id: 12718853 DOI: 10.1016/S0896-6273(03)00232-0
Date:
09-Apr-03     Release date:   20-May-03    
PROCHECK
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 Headers
 References

Protein chain
Pfam   ArchSchema ?
Q9BZR6  (RTN4R_HUMAN) -  Reticulon-4 receptor from Homo sapiens
Seq:
Struc: 		473 a.a.
284 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 

 
DOI no: 10.1016/S0896-6273(03)00232-0 Neuron 38:177-185 (2003)
PubMed id: 12718853  
 
 
Structure of the Nogo receptor ectodomain: a recognition module implicated in myelin inhibition.
X.L.He, J.F.Bazan, G.McDermott, J.B.Park, K.Wang, M.Tessier-Lavigne, Z.He, K.C.Garcia.
 
  ABSTRACT  
 
Failure of axon regeneration in the adult mammalian central nervous system (CNS) is at least partly due to inhibitory molecules associated with myelin. Recent studies suggest that an axon surface protein, the Nogo receptor (NgR), may play a role in this process through an unprecedented degree of crossreactivity with myelin-associated inhibitory ligands. Here, we report the 1.5 A crystal structure and functional characterization of a soluble extracellular domain of the human Nogo receptor. Nogo receptor adopts a leucine-rich repeat (LRR) module whose concave exterior surface contains a broad region of evolutionarily conserved patches of aromatic residues, possibly suggestive of degenerate ligand binding sites. A deep cleft at the C-terminal base of the LRR may play a role in NgR association with the p75 coreceptor. These results now provide a detailed framework for focused structure-function studies aimed at assessing the physiological relevance of NgR-mediated protein-protein interactions to axon regeneration inhibition.
 
  Selected figure(s)  
 
Figure 2.
Figure 2. The Structure of the Nogo Receptor Ligand Binding Domain(A) Side view. The N-terminal cap domain (LRRNT) is colored in purple, the leucine-rich repeats (LRR) are in cyan, and the C-terminal cap (LRRCT) domain is in pink. The high-mannose Asn-linked glycosylation sites are depicted as bonds in yellow. The central Phe residues of the “spine” are depicted as bonds in orange.(B) SIGMAA-weighted 2Fo − Fc electron density contoured at 1.5σ, showing the spine of the structure formed by a line of phenylalanine residues.(C) Face-on view into the concave belly formed by the leucine-rich repeats.(D) Structural superposition of NgR with the structure of platelet glycoprotein Ibα, showing a conserved β finger aside the concave binding face. To the right are the superpositions showing the similarities and differences between the LRRNT and LRRCT; note NgR does not contain the β switch that glycoprotein Ibα uses for ligand capture. 		Figure 4.
Figure 4. Surface Patches within the Concave Face of NgR(A) Space-filling model of the concave face showing the two surface clusters enriched in aromatic side chains that are coincident with the conservation analysis, and a very prominent acidic cavity situated at the periphery of the groove that likely mediates specificity contacts through hydrogen bonding (Trp, Phe, and Tyr in green; His in purple; acidic residues in yellow).(B) Hydrophobic patch #1 on the upper side of the concave surface, centered at Trp87, Phe63, and Ile85.(C) The acidic patch. Three aspartic acid side chains surround Ser113, forming a depressed acidic region.(D) Hydrophobic patch #2 on the lower side of the concave surface, centered at Phe184 and Leu208.(E) The hydrophobic cavity located at the LRRCT domain.(F) Crystallographic interaction utilizing the LRRCT hydrophobic cavity.
 
  The above figures are reprinted by permission from Cell Press: Neuron (2003, 38, 177-185) copyright 2003.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21280117 E.S.Henriques, R.M.Brito, H.Soares, S.Ventura, V.L.de Oliveira, and R.M.Parkhouse (2011).
Modeling of the Toll-like receptor 3 and a putative Toll-like receptor 3 antagonist encoded by the African swine fever virus.
  Protein Sci, 20, 247-255.  
  21155806 G.J.Wright, and P.Washbourne (2011).
Neurexins, neuroligins and LRRTMs: synaptic adhesion getting fishy.
  J Neurochem, 117, 765-778.  
21481769 I.Botos, D.M.Segal, and D.R.Davies (2011).
The Structural Biology of Toll-like Receptors.
  Structure, 19, 447-459.  
21308849 M.Semavina, N.Saha, M.V.Kolev, Y.Goldgur, R.J.Giger, J.P.Himanen, and D.B.Nikolov (2011).
Crystal structure of the Nogo-receptor-2.
  Protein Sci, 20, 684-689.
PDB codes: 4p8s 4p91
20697954 M.W.Poon, W.H.Tsang, S.O.Chan, H.M.Li, H.K.Ng, and M.M.Waye (2011).
Dyslexia-associated kiaa0319-like protein interacts with axon guidance receptor nogo receptor 1.
  Cell Mol Neurobiol, 31, 27-35.  
20083601 A.Joset, D.A.Dodd, S.Halegoua, and M.E.Schwab (2010).
Pincher-generated Nogo-A endosomes mediate growth cone collapse and retrograde signaling.
  J Cell Biol, 188, 271-285.  
20815818 P.H.Weinreb, D.Wen, F.Qian, C.P.Wildes, E.A.Garber, L.Walus, M.Y.Jung, J.Wang, J.K.Relton, J.Amatucci, R.Wang, F.Porreca, L.Silvian, W.Meier, R.B.Pepinsky, and D.H.Lee (2010).
Resolution of disulfide heterogeneity in Nogo receptor I fusion proteins by molecular engineering.
  Biotechnol Appl Biochem, 57, 31-45.
PDB code: 3kj4
19401181 C.Zhang, Y.Guo, N.R.Miller, and S.L.Bernstein (2009).
Optic nerve infarction and post-ischemic inflammation in the rodent model of anterior ischemic optic neuropathy (rAION).
  Brain Res, 1264, 67-75.  
19595807 I.Botos, L.Liu, Y.Wang, D.M.Segal, and D.R.Davies (2009).
The toll-like receptor 3:dsRNA signaling complex.
  Biochim Biophys Acta, 1789, 667-674.  
19452560 K.L.Hindle, J.Bella, and S.C.Lovell (2009).
Quantitative analysis and prediction of curvature in leucine-rich repeat proteins.
  Proteins, 77, 342-358.  
19420245 L.A.Robak, K.Venkatesh, H.Lee, S.J.Raiker, Y.Duan, J.Lee-Osbourne, T.Hofer, R.G.Mage, C.Rader, and R.J.Giger (2009).
Molecular basis of the interactions of the Nogo-66 receptor and its homolog NgR2 with myelin-associated glycoprotein: development of NgROMNI-Fc, a novel antagonist of CNS myelin inhibition.
  J Neurosci, 29, 5768-5783.  
19156870 R.L.Schnaar, and P.H.Lopez (2009).
Myelin-associated glycoprotein and its axonal receptors.
  J Neurosci Res, 87, 3267-3276.  
18227064 G.K.Seabold, P.Y.Wang, K.Chang, C.Y.Wang, Y.X.Wang, R.S.Petralia, and R.J.Wenthold (2008).
The SALM family of adhesion-like molecules forms heteromeric and homomeric complexes.
  J Biol Chem, 283, 8395-8405.  
18411262 G.Williams, A.Wood, E.J.Williams, Y.Gao, M.L.Mercado, A.Katz, D.Joseph-McCarthy, B.Bates, H.P.Ling, A.Aulabaugh, J.Zaccardi, Y.Xie, M.N.Pangalos, F.S.Walsh, and P.Doherty (2008).
Ganglioside inhibition of neurite outgrowth requires Nogo receptor function: identification of interaction sites and development of novel antagonists.
  J Biol Chem, 283, 16641-16652.  
19077264 H.Park, J.Huxley-Jones, R.P.Boot-Handford, P.N.Bishop, T.K.Attwood, and J.Bella (2008).
LRRCE: a leucine-rich repeat cysteine capping motif unique to the chordate lineage.
  BMC Genomics, 9, 599.  
18988857 J.K.Atwal, J.Pinkston-Gosse, J.Syken, S.Stawicki, Y.Wu, C.Shatz, and M.Tessier-Lavigne (2008).
PirB is a functional receptor for myelin inhibitors of axonal regeneration.
  Science, 322, 967-970.  
18214954 Q.R.Fan, and W.A.Hendrickson (2008).
Comparative structural analysis of the binding domain of follicle stimulating hormone receptor.
  Proteins, 72, 393-401.  
19052207 S.Budel, T.Padukkavidana, B.P.Liu, Z.Feng, F.Hu, S.Johnson, J.Lauren, J.H.Park, A.W.McGee, J.Liao, A.Stillman, J.E.Kim, B.Z.Yang, S.Sodi, J.Gelernter, H.Zhao, F.Hisama, A.F.Arnsten, and S.M.Strittmatter (2008).
Genetic variants of Nogo-66 receptor with possible association to schizophrenia block myelin inhibition of axon growth.
  J Neurosci, 28, 13161-13172.  
17848514 C.Morlot, N.M.Thielens, R.B.Ravelli, W.Hemrika, R.A.Romijn, P.Gros, S.Cusack, and A.A.McCarthy (2007).
Structural insights into the Slit-Robo complex.
  Proc Natl Acad Sci U S A, 104, 14923-14928.
PDB codes: 2v9q 2v9r 2v9s 2v9t
17704564 C.Morlot, W.Hemrika, R.A.Romijn, P.Gros, S.Cusack, and A.A.McCarthy (2007).
Production of Slit2 LRR domains in mammalian cells for structural studies and the structure of human Slit2 domain 3.
  Acta Crystallogr D Biol Crystallogr, 63, 961-968.
PDB code: 2v70
17059864 D.Puett, Y.Li, G.DeMars, K.Angelova, and F.Fanelli (2007).
A functional transmembrane complex: the luteinizing hormone receptor with bound ligand and G protein.
  Mol Cell Endocrinol, 260, 126-136.  
17803912 H.M.Kim, B.S.Park, J.I.Kim, S.E.Kim, J.Lee, S.C.Oh, P.Enkhbayar, N.Matsushima, H.Lee, O.J.Yoo, and J.O.Lee (2007).
Crystal structure of the TLR4-MD-2 complex with bound endotoxin antagonist Eritoran.
  Cell, 130, 906-917.
PDB codes: 2z62 2z63 2z64 2z65 2z66
17192264 H.M.Kim, S.C.Oh, K.J.Lim, J.Kasamatsu, J.Y.Heo, B.S.Park, H.Lee, O.J.Yoo, M.Kasahara, and J.O.Lee (2007).
Structural diversity of the hagfish variable lymphocyte receptors.
  J Biol Chem, 282, 6726-6732.
PDB codes: 2o6q 2o6r 2o6s
17486692 H.Zander, U.Reineke, J.Schneider-Mergener, and A.Skerra (2007).
Epitope mapping of the neuronal growth inhibitor Nogo-A for the Nogo receptor and the cognate monoclonal antibody IN-1 by means of the SPOT technique.
  J Mol Recognit, 20, 185-196.  
17868438 J.Dolan, K.Walshe, S.Alsbury, K.Hokamp, S.O'keeffe, T.Okafuji, S.F.Miller, G.Tear, and K.J.Mitchell (2007).
The extracellular Leucine-Rich Repeat superfamily; a comparative survey and analysis of evolutionary relationships and expression patterns.
  BMC Genomics, 8, 320.  
17189258 J.Laurén, F.Hu, J.Chin, J.Liao, M.S.Airaksinen, and S.M.Strittmatter (2007).
Characterization of myelin ligand complexes with neuronal Nogo-66 receptor family members.
  J Biol Chem, 282, 5715-5725.  
17517123 N.Matsushima, T.Tanaka, P.Enkhbayar, T.Mikami, M.Taga, K.Yamada, and Y.Kuroki (2007).
Comparative sequence analysis of leucine-rich repeats (LRRs) within vertebrate toll-like receptors.
  BMC Genomics, 8, 124.  
18043741 R.Hsu, A.Woodroffe, W.S.Lai, M.N.Cook, J.Mukai, J.P.Dunning, D.J.Swanson, J.L.Roos, G.R.Abecasis, M.Karayiorgou, and J.A.Gogos (2007).
Nogo Receptor 1 (RTN4R) as a Candidate Gene for Schizophrenia: Analysis Using Human and Mouse Genetic Approaches.
  PLoS ONE, 2, e1234.  
18177508 Y.S.Yang, and S.M.Strittmatter (2007).
The reticulons: a family of proteins with diverse functions.
  Genome Biol, 8, 234.  
16939977 B.P.Liu, W.B.Cafferty, S.O.Budel, and S.M.Strittmatter (2006).
Extracellular regulators of axonal growth in the adult central nervous system.
  Philos Trans R Soc Lond B Biol Sci, 361, 1593-1610.  
16819971 H.Kataoka, M.Yasuda, M.Iyori, K.Kiura, M.Narita, T.Nakata, and K.Shibata (2006).
Roles of N-linked glycans in the recognition of microbial lipopeptides and lipoproteins by TLR2.
  Cell Microbiol, 8, 1199-1209.  
16939978 I.C.Maier, and M.E.Schwab (2006).
Sprouting, regeneration and circuit formation in the injured spinal cord: factors and activity.
  Philos Trans R Soc Lond B Biol Sci, 361, 1611-1634.  
16629618 L.McKerracher, and H.Higuchi (2006).
Targeting Rho to stimulate repair after spinal cord injury.
  J Neurotrauma, 23, 309-317.  
17005555 L.Mosyak, A.Wood, B.Dwyer, M.Buddha, M.Johnson, A.Aulabaugh, X.Zhong, E.Presman, S.Benard, K.Kelleher, J.Wilhelm, M.L.Stahl, R.Kriz, Y.Gao, Z.Cao, H.P.Ling, M.N.Pangalos, F.S.Walsh, and W.S.Somers (2006).
The structure of the Lingo-1 ectodomain, a module implicated in central nervous system repair inhibition.
  J Biol Chem, 281, 36378-36390.
PDB code: 2id5
16877707 M.Li, J.Liu, and J.Song (2006).
Nogo goes in the pure water: solution structure of Nogo-60 and design of the structured and buffer-soluble Nogo-54 for enhancing CNS regeneration.
  Protein Sci, 15, 1835-1841.
PDB code: 2g31
16980357 M.Li, J.Liu, X.Ran, M.Fang, J.Shi, H.Qin, J.M.Goh, and J.Song (2006).
Resurrecting abandoned proteins with pure water: CD and NMR studies of protein fragments solubilized in salt-free water.
  Biophys J, 91, 4201-4209.  
16551257 Z.Pancer, and M.D.Cooper (2006).
The evolution of adaptive immunity.
  Annu Rev Immunol, 24, 497-518.  
15795223 A.N.Weber, M.C.Moncrieffe, M.Gangloff, J.L.Imler, and N.J.Gay (2005).
Ligand-receptor and receptor-receptor interactions act in concert to activate signaling in the Drosophila toll pathway.
  J Biol Chem, 280, 22793-22799.  
15647357 B.Zheng, J.Atwal, C.Ho, L.Case, X.L.He, K.C.Garcia, O.Steward, and M.Tessier-Lavigne (2005).
Genetic deletion of the Nogo receptor does not reduce neurite inhibition in vitro or promote corticospinal tract regeneration in vivo.
  Proc Natl Acad Sci U S A, 102, 1205-1210.  
16467256 D.Puett, Y.Li, K.Angelova, G.Demars, T.P.Meehan, F.Fanelli, and P.Narayan (2005).
Structure-function relationships of the luteinizing hormone receptor.
  Ann N Y Acad Sci, 1061, 41-54.  
15694321 J.B.Park, G.Yiu, S.Kaneko, J.Wang, J.Chang, X.L.He, K.C.Garcia, and Z.He (2005).
A TNF receptor family member, TROY, is a coreceptor with Nogo receptor in mediating the inhibitory activity of myelin inhibitors.
  Neuron, 45, 345-351.  
15961631 J.Choe, M.S.Kelker, and I.A.Wilson (2005).
Crystal structure of human toll-like receptor 3 (TLR3) ectodomain.
  Science, 309, 581-585.
PDB code: 1ziw
16043704 J.K.Bell, I.Botos, P.R.Hall, J.Askins, J.Shiloach, D.M.Segal, and D.R.Davies (2005).
The molecular structure of the Toll-like receptor 3 ligand-binding domain.
  Proc Natl Acad Sci U S A, 102, 10976-10980.
PDB code: 2a0z
16373579 M.N.Alder, I.B.Rogozin, L.M.Iyer, G.V.Glazko, M.D.Cooper, and Z.Pancer (2005).
Diversity and function of adaptive immune receptors in a jawless vertebrate.
  Science, 310, 1970-1973.  
15173186 A.N.Weber, M.A.Morse, and N.J.Gay (2004).
Four N-linked glycosylation sites in human toll-like receptor 2 cooperate to direct efficient biosynthesis and secretion.
  J Biol Chem, 279, 34589-34594.  
15345720 G.Kleinau, H.Jäschke, S.Neumann, J.Lättig, R.Paschke, and G.Krause (2004).
Identification of a novel epitope in the thyroid-stimulating hormone receptor ectodomain acting as intramolecular signaling interface.
  J Biol Chem, 279, 51590-51600.  
15496984 J.A.Howitt, N.J.Clout, and E.Hohenester (2004).
Binding site for Robo receptors revealed by dissection of the leucine-rich repeat region of Slit.
  EMBO J, 23, 4406-4412.
PDB code: 1w8a
15199958 K.Inamori, S.Ariki, and S.Kawabata (2004).
A Toll-like receptor in horseshoe crabs.
  Immunol Rev, 198, 106-115.  
15018947 M.E.Schwab (2004).
Nogo and axon regeneration.
  Curr Opin Neurobiol, 14, 118-124.  
15317586 M.Li, J.Shi, Z.Wei, F.Y.Teng, B.L.Tang, and J.Song (2004).
Structural characterization of the human Nogo-A functional domains. Solution structure of Nogo-40, a Nogo-66 receptor antagonist enhancing injured spinal cord regeneration.
  Eur J Biochem, 271, 3512-3522.  
14747988 P.Enkhbayar, M.Kamiya, M.Osaki, T.Matsumoto, and N.Matsushima (2004).
Structural principles of leucine-rich repeat (LRR) proteins.
  Proteins, 54, 394-403.  
15501918 P.G.Scott, P.A.McEwan, C.M.Dodd, E.M.Bergmann, P.N.Bishop, and J.Bella (2004).
Crystal structure of the dimeric protein core of decorin, the archetypal small leucine-rich repeat proteoglycan.
  Proc Natl Acad Sci U S A, 101, 15633-15638.
PDB codes: 1xcd 1xec 1xku
15297463 W.Li, L.Walus, S.A.Rabacchi, A.Jirik, E.Chang, J.Schauer, B.H.Zheng, N.J.Benedetti, B.P.Liu, E.Choi, D.Worley, L.Silvian, W.Mo, C.Mullen, W.Yang, S.M.Strittmatter, D.W.Sah, B.Pepinsky, and D.H.Lee (2004).
A neutralizing anti-Nogo66 receptor monoclonal antibody reverses inhibition of neurite outgrowth by central nervous system myelin.
  J Biol Chem, 279, 43780-43788.  
15217336 Z.He, and V.Koprivica (2004).
The Nogo signaling pathway for regeneration block.
  Annu Rev Neurosci, 27, 341-368.  
12718850 C.J.Woolf (2003).
No Nogo: now where to go?
  Neuron, 38, 153-156.  
14668808 D.H.Lee, S.M.Strittmatter, and D.W.Sah (2003).
Targeting the Nogo receptor to treat central nervous system injuries.
  Nat Rev Drug Discov, 2, 872-878.  
14598291 E.M.Grados-Munro, and A.E.Fournier (2003).
Myelin-associated inhibitors of axon regeneration.
  J Neurosci Res, 74, 479-485.  
14552836 J.K.Bell, G.E.Mullen, C.A.Leifer, A.Mazzoni, D.R.Davies, and D.M.Segal (2003).
Leucine-rich repeats and pathogen recognition in Toll-like receptors.
  Trends Immunol, 24, 528-533.  
12839991 W.A.Barton, B.P.Liu, D.Tzvetkova, P.D.Jeffrey, A.E.Fournier, D.Sah, R.Cate, S.M.Strittmatter, and D.B.Nikolov (2003).
Structure and axon outgrowth inhibitor binding of the Nogo-66 receptor and related proteins.
  EMBO J, 22, 3291-3302.
PDB code: 1p8t
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 codes are shown on the right.

 

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