PDBsum entry 1rew

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protein Protein-protein interface(s) links
Hormone/growth factor/signaling protein PDB id
Jmol PyMol
Protein chains
103 a.a. *
86 a.a. *
Waters ×185
* Residue conservation analysis
PDB id:
Name: Hormone/growth factor/signaling protein
Title: Structural refinement of the complex of bone morphogenetic p and its type ia receptor
Structure: Bone morphogenetic protein 2. Chain: a, b. Fragment: mature part. Engineered: yes. Bone morphogenetic protein receptor type ia. Chain: c, d. Fragment: extracellular domain. Synonym: serine/threonine-protein kinase receptor r5. Skr5. Receptor-like kinase 3. Alk-3. Activin a receptor. Type ii
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562.
Biol. unit: Tetramer (from PQS)
1.86Å     R-factor:   0.208     R-free:   0.229
Authors: S.Keller,J.Nickel,J.-L.Zhang,W.Sebald,T.D.Mueller
Key ref:
S.Keller et al. (2004). Molecular recognition of BMP-2 and BMP receptor IA. Nat Struct Mol Biol, 11, 481-488. PubMed id: 15064755 DOI: 10.1038/nsmb756
07-Nov-03     Release date:   04-May-04    
Go to PROCHECK summary

Protein chains
Pfam   ArchSchema ?
P12643  (BMP2_HUMAN) -  Bone morphogenetic protein 2
396 a.a.
103 a.a.
Protein chains
Pfam   ArchSchema ?
P36894  (BMR1A_HUMAN) -  Bone morphogenetic protein receptor type-1A
532 a.a.
86 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: Chains C, D: E.C.  - Receptor protein serine/threonine kinase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: ATP + [receptor-protein] = ADP + [receptor-protein] phosphate
+ [receptor-protein]
+ [receptor-protein] phosphate
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     membrane   1 term 
  Biological process     transmembrane receptor protein serine/threonine kinase signaling pathway   1 term 
  Biochemical function     growth factor activity     4 terms  


    Added reference    
DOI no: 10.1038/nsmb756 Nat Struct Mol Biol 11:481-488 (2004)
PubMed id: 15064755  
Molecular recognition of BMP-2 and BMP receptor IA.
S.Keller, J.Nickel, J.L.Zhang, W.Sebald, T.D.Mueller.
Bone morphogenetic protein-2 (BMP-2) and other members of the TGF-beta superfamily regulate the development, maintenance and regeneration of tissues and organs. Binding epitopes for these extracellular signaling proteins have been defined, but hot spots specifying binding affinity and specificity have so far not been identified. In this study, mutational and structural analyses show that epitopes of BMP-2 and the BRIA receptor form a new type of protein-protein interface. The main chain atoms of Leu 51 and Asp53 of BMP-2 represent a hot spot of binding to BRIA. The BMP-2 variant L51P was deficient in type I receptor binding only, whereas its overall structure and its binding to type II receptors and modulator proteins, such as noggin, were unchanged. Thus, the L51P substitution converts BMP-2 into a receptor-inactive inhibitor of noggin. These results are relevant for other proteins of the TGF-beta superfamily and provide useful clues for structure-based drug design.
  Selected figure(s)  
Figure 2.
Figure 2. Central hydrogen-bonding network in the interface of BMP-2 and BRIA. (a) The pre-helix loop of BMP-2 is shown in stereo as ball-and-stick for residues Pro48 -Asp53. Secondary structure elements of BRIA are shown in green, with side chains of contacting residues presented as ball-and-stick. The hydrogen bonds that were subjected to mutagenesis--Leu51 -Gln86, Asp53 -Thr55 and Asp53 -Cys77--are shown by dashed lines. The quality of the electron density map in this area is shown by a 2F[obs] - F[calc] electron density map at a 1.4- contour level. (b) Hydrogen-bonding network of the buried water molecules in the interface of BMP-2 and BRIA. Three water molecules form a network connecting NH[2] of BRIA Gln86 with the backbone amides of BMP-2 Asn56 and Ser57. The exchange of these water molecules is limited by the side chains of BRIA Lys76 and Glu81 blocking the entrance to this cavity. The water molecule hydrogen-bonded to the BRIA Gln86 side chain carboxyl group (OE1) is locked in place by Phe49 and Pro50 of BMP-2. Figure as produced with BOBSCRIPT38, MOLSCRIPT35 and Raster3D^36 software.
Figure 3.
Figure 3. Comparison of BMP-2 bound to BRIA and BMP-2 L51P. (a) Stereo view of the pre-helix loop segment showing the crystal structure of BMP-2 L51P (atom colors: N, dark blue; O, dark red; C, light green) superimposed onto BMP-2 (atom colors: N, light blue; O, orange; C, gray) in complex with BRIA. The hydrogen bond between wild-type BMP-2 Leu51 and BRIA Gln86 is shown by dashed lines. Replacement of Leu51 by proline is likely to cause steric interference (shown by red circles), owing to the ring structure of the proline residue oriented toward Gln86 of BRIA. (b) Comparison of the temperature factors (B-factors) for BMP-2 wild type in the free (PDB entry 3BMP) and bound forms. The region for the pre-helix loop is shown in gray. Figure produced with MOLSCRIPT35 software.
  The above figures are reprinted by permission from Macmillan Publishers Ltd: Nat Struct Mol Biol (2004, 11, 481-488) copyright 2004.  
  Figures were selected by the author.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
  21488130 N.Kamiya, and Y.Mishina (2011).
New insights on the roles of BMP signaling in bone-A review of recent mouse genetic studies.
  Biofactors, 37, 75-82.  
20545624 C.C.Rider, and B.Mulloy (2010).
Bone morphogenetic protein and growth differentiation factor cytokine families and their protein antagonists.
  Biochem J, 429, 1.  
20886103 J.L.Zhang, L.J.Patterson, L.Y.Qiu, D.Graziussi, W.Sebald, and M.Hammerschmidt (2010).
Binding between Crossveinless-2 and Chordin von Willebrand factor type C domains promotes BMP signaling by blocking Chordin activity.
  PLoS One, 5, e12846.  
20674464 J.W.Lowery, and Caestecker (2010).
BMP signaling in vascular development and disease.
  Cytokine Growth Factor Rev, 21, 287-298.  
19874086 N.Kamiya, T.Kobayashi, Y.Mochida, P.B.Yu, M.Yamauchi, H.M.Kronenberg, and Y.Mishina (2010).
Wnt inhibitors Dkk1 and Sost are downstream targets of BMP signaling through the type IA receptor (BMPRIA) in osteoblasts.
  J Bone Miner Res, 25, 200-210.  
  20927405 S.Harth, A.Kotzsch, J.Hu, W.Sebald, and T.D.Mueller (2010).
A selection fit mechanism in BMP receptor IA as a possible source for BMP ligand-receptor promiscuity.
  PLoS One, 5, 0.
PDB code: 3nh7
19229295 A.Kotzsch, J.Nickel, A.Seher, W.Sebald, and T.D.Müller (2009).
Crystal structure analysis reveals a spring-loaded latch as molecular mechanism for GDF-5-type I receptor specificity.
  EMBO J, 28, 937-947.
PDB code: 3evs
19644449 J.N.Cash, C.A.Rejon, A.C.McPherron, D.J.Bernard, and T.B.Thompson (2009).
The structure of myostatin:follistatin 288: insights into receptor utilization and heparin binding.
  EMBO J, 28, 2662-2676.
PDB code: 3hh2
19926516 J.Nickel, W.Sebald, J.C.Groppe, and T.D.Mueller (2009).
Intricacies of BMP receptor assembly.
  Cytokine Growth Factor Rev, 20, 367-377.  
19735544 K.Heinecke, A.Seher, W.Schmitz, T.D.Mueller, W.Sebald, and J.Nickel (2009).
Receptor oligomerization and beyond: a case study in bone morphogenetic proteins.
  BMC Biol, 7, 59.  
19424823 K.P.Holbourn, B.Perbal, and K.Ravi Acharya (2009).
Proteins on the catwalk: modelling the structural domains of the CCN family of proteins.
  J Cell Commun Signal, 3, 25-41.  
19502096 L.David, J.J.Feige, and S.Bailly (2009).
Emerging role of bone morphogenetic proteins in angiogenesis.
  Cytokine Growth Factor Rev, 20, 203-212.  
19169249 L.T.MacNeil, W.R.Hardy, T.Pawson, J.L.Wrana, and J.G.Culotti (2009).
UNC-129 regulates the balance between UNC-40 dependent and independent UNC-5 signaling pathways.
  Nat Neurosci, 12, 150-155.  
19910235 M.H.Alaoui-Ismaili, and D.Falb (2009).
Design of second generation therapeutic recombinant bone morphogenetic proteins.
  Cytokine Growth Factor Rev, 20, 501-507.  
19956691 P.Seemann, A.Brehm, J.König, C.Reissner, S.Stricker, P.Kuss, J.Haupt, S.Renninger, J.Nickel, W.Sebald, J.C.Groppe, F.Plöger, J.Pohl, M.Schmidt-von Kegler, M.Walther, I.Gassner, C.Rusu, A.R.Janecke, K.Dathe, and S.Mundlos (2009).
Mutations in GDF5 reveal a key residue mediating BMP inhibition by NOGGIN.
  PLoS Genet, 5, e1000747.  
18485004 A.Galat, G.Gross, P.Drevet, A.Sato, and A.Ménez (2008).
Conserved structural determinants in three-fingered protein domains.
  FEBS J, 275, 3207-3225.  
18160401 A.Kotzsch, J.Nickel, A.Seher, K.Heinecke, L.van Geersdaele, T.Herrmann, W.Sebald, and T.D.Mueller (2008).
Structure analysis of bone morphogenetic protein-2 type I receptor complexes reveals a mechanism of receptor inactivation in juvenile polyposis syndrome.
  J Biol Chem, 283, 5876-5887.
PDB codes: 2qj9 2qja 2qjb
18243111 J.Groppe, C.S.Hinck, P.Samavarchi-Tehrani, C.Zubieta, J.P.Schuermann, A.B.Taylor, P.M.Schwarz, J.L.Wrana, and A.P.Hinck (2008).
Cooperative assembly of TGF-beta superfamily signaling complexes is mediated by two disparate mechanisms and distinct modes of receptor binding.
  Mol Cell, 29, 157-168.
PDB code: 2pjy
18789696 K.P.Holbourn, K.R.Acharya, and B.Perbal (2008).
The CCN family of proteins: structure-function relationships.
  Trends Biochem Sci, 33, 461-473.  
18768470 R.Stamler, H.T.Keutmann, Y.Sidis, C.Kattamuri, A.Schneyer, and T.B.Thompson (2008).
  J Biol Chem, 283, 32831-32838.
PDB code: 3b4v
18056265 R.V.Korupolu, U.Muenster, J.D.Read, W.Vale, and W.H.Fischer (2008).
Activin A/bone morphogenetic protein (BMP) chimeras exhibit BMP-like activity and antagonize activin and myostatin.
  J Biol Chem, 283, 3782-3790.  
17239579 D.Reichmann, O.Rahat, M.Cohen, H.Neuvirth, and G.Schreiber (2007).
The molecular architecture of protein-protein binding sites.
  Curr Opin Struct Biol, 17, 67-76.  
17295905 D.Weber, A.Kotzsch, J.Nickel, S.Harth, A.Seher, U.Mueller, W.Sebald, and T.D.Mueller (2007).
A silent H-bond can be mutationally activated for high-affinity interaction of BMP-2 and activin type IIB receptor.
  BMC Struct Biol, 7, 6.
PDB codes: 2h62 2h64
17483092 J.L.Zhang, Y.Huang, L.Y.Qiu, J.Nickel, and W.Sebald (2007).
von Willebrand factor type C domain-containing proteins regulate bone morphogenetic protein signaling through different recognition mechanisms.
  J Biol Chem, 282, 20002-20014.  
17409095 T.F.Lerch, S.Shimasaki, T.K.Woodruff, and T.S.Jardetzky (2007).
Structural and biophysical coupling of heparin and activin binding to follistatin isoform functions.
  J Biol Chem, 282, 15930-15939.
PDB code: 2p6a
16528751 H.Xin, Y.Li, X.Chen, and M.Chopp (2006).
Bone marrow stromal cells induce BMP2/4 production in oxygen-glucose-deprived astrocytes, which promotes an astrocytic phenotype in adult subventricular progenitor cells.
  J Neurosci Res, 83, 1485-1493.  
16014698 K.W.Kjaer, H.Eiberg, L.Hansen, C.B.van der Hagen, K.Rosendahl, N.Tommerup, and S.Mundlos (2006).
A mutation in the receptor binding site of GDF5 causes Mohr-Wriedt brachydactyly type A2.
  J Med Genet, 43, 225-231.  
16127465 P.Seemann, R.Schwappacher, K.W.Kjaer, D.Krakow, K.Lehmann, K.Dawson, S.Stricker, J.Pohl, F.Plöger, E.Staub, J.Nickel, W.Sebald, P.Knaus, and S.Mundlos (2005).
Activating and deactivating mutations in the receptor interaction site of GDF5 cause symphalangism or brachydactyly type A2.
  J Clin Invest, 115, 2373-2381.  
16252250 R.L.Rich, and D.G.Myszka (2005).
Survey of the year 2004 commercial optical biosensor literature.
  J Mol Recognit, 18, 431-478.  
16129674 U.Muenster, C.A.Harrison, C.Donaldson, W.Vale, and W.H.Fischer (2005).
An activin-A/C chimera exhibits activin and myostatin antagonistic properties.
  J Biol Chem, 280, 36626-36632.  
16212511 X.H.Feng, and R.Derynck (2005).
Specificity and versatility in tgf-beta signaling through Smads.
  Annu Rev Cell Dev Biol, 21, 659-693.  
15466413 J.M.O'Leary, J.M.Hamilton, C.M.Deane, N.V.Valeyev, L.J.Sandell, and A.K.Downing (2004).
Solution structure and dynamics of a prototypical chordin-like cysteine-rich repeat (von Willebrand Factor type C module) from collagen IIA.
  J Biol Chem, 279, 53857-53866.
PDB code: 1u5m
15449706 W.Sebald, J.Nickel, J.L.Zhang, and T.D.Mueller (2004).
Molecular recognition in bone morphogenetic protein (BMP)/receptor interaction.
  Biol Chem, 385, 697-710.  
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.