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PDBsum entry 2h62

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protein Protein-protein interface(s) links
Hormone/growth factor PDB id
2h62
Jmol
Contents
Protein chains
104 a.a. *
84 a.a. *
93 a.a. *
Waters ×288
* Residue conservation analysis
PDB id:
2h62
Name: Hormone/growth factor
Title: Crystal structure of a ternary ligand-receptor complex of bmp-2
Structure: Bone morphogenetic protein 2. Chain: a, b. Synonym: bmp-2, bmp-2a. Engineered: yes. Bone morphogenetic protein receptor type ia. Chain: c. Fragment: extracellular domain. Synonym: serine/threonine-protein kinase receptor r5, skr5, activin receptor-like kinase 3, alk-3, cd292 antigen.
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: bmp2, bmp2a. Expressed in: escherichia coli. Expression_system_taxid: 562. Gene: bmpr1a, acvrlk3, alk3. Expression_system_taxid: 562
Resolution:
1.85Å     R-factor:   0.216     R-free:   0.225
Authors: T.D.Mueller
Key ref: D.Weber et al. (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. PubMed id: 17295905
Date:
30-May-06     Release date:   10-Apr-07    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P12643  (BMP2_HUMAN) -  Bone morphogenetic protein 2
Seq:
Struc:
396 a.a.
104 a.a.
Protein chain
Pfam   ArchSchema ?
P36894  (BMR1A_HUMAN) -  Bone morphogenetic protein receptor type-1A
Seq:
Struc:
 
Seq:
Struc:
532 a.a.
84 a.a.
Protein chain
Pfam   ArchSchema ?
Q13705  (AVR2B_HUMAN) -  Activin receptor type-2B
Seq:
Struc:
512 a.a.
93 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: Chains C, D: E.C.2.7.11.30  - Receptor protein serine/threonine kinase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: ATP + [receptor-protein] = ADP + [receptor-protein] phosphate
ATP
+ [receptor-protein]
= ADP
+ [receptor-protein] phosphate
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     extracellular region   2 terms 
  Biological process     transmembrane receptor protein serine/threonine kinase signaling pathway   1 term 
  Biochemical function     growth factor activity     5 terms  

 

 
    Added reference    
 
 
BMC Struct Biol 7:6 (2007)
PubMed id: 17295905  
 
 
A silent H-bond can be mutationally activated for high-affinity interaction of BMP-2 and activin type IIB receptor.
D.Weber, A.Kotzsch, J.Nickel, S.Harth, A.Seher, U.Mueller, W.Sebald, T.D.Mueller.
 
  ABSTRACT  
 
BACKGROUND: Bone morphogenetic proteins (BMPs) are key regulators in the embryonic development and postnatal tissue homeostasis in all animals. Loss of function or dysregulation of BMPs results in severe diseases or even lethality. Like transforming growth factors beta (TGF-betas), activins, growth and differentiation factors (GDFs) and other members of the TGF-beta superfamily, BMPs signal by assembling two types of serine/threonine-kinase receptor chains to form a hetero-oligomeric ligand-receptor complex. BMP ligand receptor interaction is highly promiscuous, i.e. BMPs bind more than one receptor of each subtype, and a receptor bind various ligands. The activin type II receptors are of particular interest, since they bind a large number of diverse ligands. In addition they act as high-affinity receptors for activins but are also low-affinity receptors for BMPs. ActR-II and ActR-IIB therefore represent an interesting example how affinity and specificity might be generated in a promiscuous background. RESULTS: Here we present the high-resolution structures of the ternary complexes of wildtype and a variant BMP-2 bound to its high-affinity type I receptor BMPR-IA and its low-affinity type II receptor ActR-IIB and compare them with the known structures of binary and ternary ligand-receptor complexes of BMP-2. In contrast to activin or TGF-beta3 no changes in the dimer architecture of the BMP-2 ligand occur upon complex formation. Functional analysis of the ActR-IIB binding epitope shows that hydrophobic interactions dominate in low-affinity binding of BMPs; polar interactions contribute only little to binding affinity. However, a conserved H-bond in the center of the type II ligand-receptor interface, which does not contribute to binding in the BMP-2 - ActR-IIB interaction can be mutationally activated resulting in a BMP-2 variant with high-affinity for ActR-IIB. Further mutagenesis studies were performed to elucidate the binding mechanism allowing us to construct BMP-2 variants with defined type II receptor binding properties. CONCLUSION: Binding specificity of BMP-2 for its three type II receptors BMPR-II, Act-RII and ActR-IIB is encoded on single amino acid level. Exchange of only one or two residues results in BMP-2 variants with a dramatically altered type II receptor specificity profile, possibly allowing construction of BMP-2 variants that address a single type II receptor. The structure-/function studies presented here revealed a new mechanism, in which the energy contribution of a conserved H-bond is modulated by surrounding intramolecular interactions to achieve a switch between low- and high-affinity binding.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
20949628 S.J.Lubbe, A.M.Pittman, C.Matijssen, P.Twiss, B.Olver, A.Lloyd, M.Qureshi, N.Brown, E.Nye, G.Stamp, J.Blagg, and R.S.Houlston (2011).
Evaluation of germline BMP4 mutation as a cause of colorectal cancer.
  Hum Mutat, 32, E1928-E1938.  
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.  
20629020 L.Calvanese, D.Marasco, N.Doti, A.Saporito, G.D'Auria, L.Paolillo, M.Ruvo, and L.Falcigno (2010).
Structural investigations on the Nodal-Cripto binding: a theoretical and experimental approach.
  Biopolymers, 93, 1011-1021.  
20667411 O.F.Zouani, C.Chollet, B.Guillotin, and M.C.Durrieu (2010).
Differentiation of pre-osteoblast cells on poly(ethylene terephthalate) grafted with RGD and/or BMPs mimetic peptides.
  Biomaterials, 31, 8245-8253.  
  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
20861306 W.J.Kuo, M.A.Digman, and A.D.Lander (2010).
Heparan sulfate acts as a bone morphogenetic protein coreceptor by facilitating ligand-induced receptor hetero-oligomerization.
  Mol Biol Cell, 21, 4028-4041.  
19390888 Z.Xu, X.W.Liu, Y.S.Ma, and H.W.Gao (2010).
Interaction of nano-TiO(2) with lysozyme: insights into the enzyme toxicity of nanosized particles.
  Environ Sci Pollut Res Int, 17, 798-806.  
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.  
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.  
19377468 S.C.Little, and M.C.Mullins (2009).
Bone morphogenetic protein heterodimers assemble heteromeric type I receptor complexes to pattern the dorsoventral axis.
  Nat Cell Biol, 11, 637-643.  
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.  
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
  18391434 L.Y.Qiu, J.L.Zhang, A.Kotzsch, W.Sebald, and T.D.Mueller (2008).
Crystallization and preliminary X-ray analysis of the complex of the first von Willebrand type C domain bound to bone morphogenetic protein 2.
  Acta Crystallogr Sect F Struct Biol Cryst Commun, 64, 307-312.  
18768470 R.Stamler, H.T.Keutmann, Y.Sidis, C.Kattamuri, A.Schneyer, and T.B.Thompson (2008).
The Structure of FSTL3{middle dot}Activin A Complex: DIFFERENTIAL BINDING OF N-TERMINAL DOMAINS INFLUENCES FOLLISTATIN-TYPE ANTAGONIST SPECIFICITY.
  J Biol Chem, 283, 32831-32838.
PDB code: 3b4v
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.  
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.