PDBsum entry 2qcq

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protein Protein-protein interface(s) links
Signaling protein PDB id
Protein chains
107 a.a. *
Waters ×98
* Residue conservation analysis
PDB id:
Name: Signaling protein
Title: Crystal structure of bone morphogenetic protein-3 (bmp-3)
Structure: Bone morphogenetic protein 3. Chain: a, b. Synonym: bmp-3, osteogenin, bmp-3a. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: bmp3. Expressed in: escherichia coli bl21. Expression_system_taxid: 511693.
2.21Å     R-factor:   0.230     R-free:   0.257
Authors: G.P.Allendorph
Key ref: G.P.Allendorph et al. (2007). BMP-3 and BMP-6 structures illuminate the nature of binding specificity with receptors. Biochemistry, 46, 12238-12247. PubMed id: 17924656 DOI: 10.1021/bi700907k
19-Jun-07     Release date:   23-Oct-07    
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Protein chains
Pfam   ArchSchema ?
P12645  (BMP3_HUMAN) -  Bone morphogenetic protein 3
472 a.a.
107 a.a.
Key:    PfamA domain  PfamB domain  Secondary structure  CATH domain

 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     extracellular region   1 term 
  Biochemical function     growth factor activity     1 term  


DOI no: 10.1021/bi700907k Biochemistry 46:12238-12247 (2007)
PubMed id: 17924656  
BMP-3 and BMP-6 structures illuminate the nature of binding specificity with receptors.
G.P.Allendorph, M.J.Isaacs, Y.Kawakami, J.C.Izpisua Belmonte, S.Choe.
Bone morphogenetic proteins (BMPs) are extracellular messenger ligands involved in controlling a wide array of developmental and intercellular signaling processes. To initiate their specific intracellular signaling pathways, the ligands recognize and bind two structurally related serine/threonine kinase receptors, termed type I and type II, on the cell surface. Here, we present the crystal structures of BMP-3 and BMP-6, of which BMP-3 has remained poorly understood with respect to its receptor identity, affinity, and specificity. Using surface plasmon resonance (BIAcore) we show that BMP-3 binds Activin Receptor type II (ActRII) with Kd approximately 1.8 microM but ActRIIb with 30-fold higher affinity at Kd approximately 53 nM. This low affinity for ActRII may involve Ser-28 and Asp-33 of BMP-3, which are found only in BMP-3's type II receptor-binding interfaces. Point mutations of either residue to alanine results in up to 20-fold higher affinity to either receptor. We further demonstrate by Smad-based whole cell luciferase assays that the increased affinity of BMP-3S28A to ActRII enables the ligand's signaling ability to a level comparable to that of BMP-6. Focusing on BMP-3's preference for ActRIIb, we find that Lys-76 of ActRII and the structurally equivalent Glu-76 of ActRIIb are distinct between the two receptors. We demonstrate that ActRIIbE76K and ActRII bind BMP-3 with similar affinity, indicating BMP-3 receptor specificity is controlled by the interaction of Lys-30 of BMP-3 with Glu-76 of ActRIIb. These studies illustrate how a single amino acid can regulate the specificity of ligand-receptor binding and potentially alter biological signaling and function in vivo.

Literature references that cite this PDB file's key reference

  PubMed id Reference
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.  
21054789 G.Szláma, K.Kondás, M.Trexler, and L.Patthy (2010).
WFIKKN1 and WFIKKN2 bind growth factors TGFβ1, BMP2 and BMP4 but do not inhibit their signalling activity.
  FEBS J, 277, 5040-5050.  
20194748 S.Vallet, S.Mukherjee, N.Vaghela, T.Hideshima, M.Fulciniti, S.Pozzi, L.Santo, D.Cirstea, K.Patel, A.R.Sohani, A.Guimaraes, W.Xie, D.Chauhan, J.A.Schoonmaker, E.Attar, M.Churchill, E.Weller, N.Munshi, J.S.Seehra, R.Weissleder, K.C.Anderson, D.T.Scadden, and N.Raje (2010).
Activin A promotes multiple myeloma-induced osteolysis and is a promising target for myeloma bone disease.
  Proc Natl Acad Sci U S A, 107, 5124-5129.  
19720031 B.Bragdon, S.Thinakaran, J.Bonor, T.M.Underhill, N.O.Petersen, and A.Nohe (2009).
FRET reveals novel protein-receptor interaction of bone morphogenetic proteins receptors and adaptor protein 2 at the cell surface.
  Biophys J, 97, 1428-1435.  
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.  
19653325 L.W.Gamer, K.Cox, J.M.Carlo, and V.Rosen (2009).
Overexpression of BMP3 in the developing skeleton alters endochondral bone formation resulting in spontaneous rib fractures.
  Dev Dyn, 238, 2374-2381.  
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.  
19900832 S.Vukicevic, and L.Grgurevic (2009).
BMP-6 and mesenchymal stem cell differentiation.
  Cytokine Growth Factor Rev, 20, 441-448.  
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.  
18489005 L.W.Gamer, V.Ho, K.Cox, and V.Rosen (2008).
Expression and function of BMP3 during chick limb development.
  Dev Dyn, 237, 1691-1698.  
18460605 R.S.Pearsall, E.Canalis, M.Cornwall-Brady, K.W.Underwood, B.Haigis, J.Ucran, R.Kumar, E.Pobre, A.Grinberg, E.D.Werner, V.Glatt, L.Stadmeyer, D.Smith, J.Seehra, and M.L.Bouxsein (2008).
A soluble activin type IIA receptor induces bone formation and improves skeletal integrity.
  Proc Natl Acad Sci U S A, 105, 7082-7087.  
18397882 Y.Makanji, K.L.Walton, M.C.Wilce, K.L.Chan, D.M.Robertson, and C.A.Harrison (2008).
Suppression of inhibin A biological activity by alterations in the binding site for betaglycan.
  J Biol Chem, 283, 16743-16751.  
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.