PDBsum entry 1waq

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Growth factor PDB id
Protein chain
104 a.a. *
MPD ×3
Waters ×23
* Residue conservation analysis
PDB id:
Name: Growth factor
Title: Crystal structure of human growth and differentiation factor 5 (gdf-5)
Structure: Growth/differentiation factor 5. Chain: a. Fragment: residues 387-501 (residues 6-120 of mature gdf-5) synonym: gdf-5, cartilage-derived morphogenetic protein 1, engineered: yes. Other_details: dimeric connected through intermolecular dis bond between cys 84
Source: Homo sapiens. Human. Organism_taxid: 9606. Cell: fibroblast. Expressed in: escherichia coli. Expression_system_taxid: 562.
Biol. unit: Dimer (from PDB file)
2.28Å     R-factor:   0.223     R-free:   0.237
Authors: T.D.Mueller,J.Nickel,W.Sebald
Key ref:
J.Nickel et al. (2005). A single residue of GDF-5 defines binding specificity to BMP receptor IB. J Mol Biol, 349, 933-947. PubMed id: 15890363 DOI: 10.1016/j.jmb.2005.04.015
27-Oct-04     Release date:   19-May-05    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
P43026  (GDF5_HUMAN) -  Growth/differentiation factor 5
501 a.a.
104 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: 10.1016/j.jmb.2005.04.015 J Mol Biol 349:933-947 (2005)
PubMed id: 15890363  
A single residue of GDF-5 defines binding specificity to BMP receptor IB.
J.Nickel, A.Kotzsch, W.Sebald, T.D.Mueller.
Growth and differentiation factor 5 (GDF-5), a member of the TGF-beta superfamily, is involved in many developmental processes, like chondrogenesis and joint formation. Mutations in GDF-5 lead to diseases, e.g. chondrodysplasias like Hunter-Thompson, Grebe and DuPan syndromes and brachydactyly. Similar to other TGF-beta superfamily members, GDF-5 transmits signals through binding to two different types of membrane-bound serine-/threonine-kinase receptors termed type I and type II. In contrast to the large number of ligands, only seven type I and five type II receptors have been identified to date, implicating a limited promiscuity in ligand-receptor interaction. However, in contrast to other members of the TGF-beta superfamily, GDF-5 shows a pronounced specificity in type I receptor interaction in cross-link experiments binding only to BMP receptor IB (BMPR-IB). In mice, deletion of either GDF-5 or BMPR-IB results in a similar phenotype, indicating that GDF-5 signaling is highly dependent on BMPR-IB. Here, we demonstrate by biosensor analysis that GDF-5 also binds to BMP receptor IA (BMPR-IA) but with approximately 12-fold lower affinity. Structural and mutational analyses revealed a single residue of GDF-5, Arg57 located in the pre-helix loop, being solely responsible for the high binding specificity to BMPR-IB. In contrast to wild-type GDF-5, variant GDF-5R57A interacts with BMPR-IA and BMPR-IB with a comparable high binding affinity. These results provide important insights into how receptor-binding specificity is generated at the molecular level and might be useful for the generation of receptor subtype specific activators or inhibitors.
  Selected figure(s)  
Figure 3.
Figure 3. Modeling of the pre-helix loop conformation of GDF-5 in the bound state. (a) The backbone and side-chain conformation of several residues located in the pre-helix loop of free GDF-5 (carbon atoms in gray, GDF-5 in bound conformation is shown with carbon atoms in green) were adapted to the conformation observed in the structure of the complex of BMP-2 bound to BMPR-IA (PDB entry 1REW). Residues Phe54 and Pro55 of GDF-5 were modeled manually to adapt to the torsion angles observed in BMP-2 bound to BMPR-IA. The side-chain conformation of Arg57 was changed to adopt an all-trans conformation to avoid a steric clash with atoms of the receptor molecule upon docking. (b) BMP-2 in the free state is shown with carbon atoms indicated in gray; BMP-2 in the bound conformation is shown with carbon atoms colored green. The change in conformation is rather small; comparing the structures of BMP-2 in its free form (PDB entry 3BMP) and bound form (PDB entry 1REW) reveals a similar change in structure suggesting a sort of induced fit upon receptor binding.
Figure 4.
Figure 4. Structural differences for the BMP tryptophan sequence signature. The b-sheets of fingers 1 and 2 of GDF-5 (blue), BMP-2 (green) and BMP-7 (red) are superimposed, revealing the structural differences in the loop conformations of fingers 1 and 2. Although the double tryptophan pattern is highly conserved in the TGF-b superfamily, the structural alignment shows significant differences in their main and side-chain conformations. The differences result in a different shape of the hydrophobic pocket, which is formed partially by the tryptophan rings.
  The above figures are reprinted by permission from Elsevier: J Mol Biol (2005, 349, 933-947) copyright 2005.  
  Figures were selected by an automated process.  

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.  
20170953 P.Kasten, I.Beyen, D.Bormann, R.Luginbühl, F.Plöger, and W.Richter (2010).
The effect of two point mutations in GDF-5 on ectopic bone formation in a beta-tricalciumphosphate scaffold.
  Biomaterials, 31, 3878-3884.  
19590978 Y.F.Liu, L.S.Zan, K.Li, S.P.Zhao, Y.P.Xin, Q.Lin, W.Q.Tian, and Z.W.Wang (2010).
A novel polymorphism of GDF5 gene and its association with body measurement traits in Bos taurus and Bos indicus breeds.
  Mol Biol Rep, 37, 429-434.  
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
19479880 E.Evangelou, K.Chapman, I.Meulenbelt, F.B.Karassa, J.Loughlin, A.Carr, M.Doherty, S.Doherty, J.J.Gómez-Reino, A.Gonzalez, B.V.Halldorsson, V.B.Hauksson, A.Hofman, D.J.Hart, S.Ikegawa, T.Ingvarsson, Q.Jiang, I.Jonsdottir, H.Jonsson, H.J.Kerkhof, M.Kloppenburg, N.E.Lane, J.Li, R.J.Lories, J.B.van Meurs, A.Näkki, M.C.Nevitt, J.Rodriguez-Lopez, D.Shi, P.E.Slagboom, K.Stefansson, A.Tsezou, G.A.Wallis, C.M.Watson, T.D.Spector, A.G.Uitterlinden, A.M.Valdes, and J.P.Ioannidis (2009).
Large-scale analysis of association between GDF5 and FRZB variants and osteoarthritis of the hip, knee, and hand.
  Arthritis Rheum, 60, 1710-1721.  
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.  
19555855 N.W.Morrell, S.Adnot, S.L.Archer, J.Dupuis, P.L.Jones, M.R.MacLean, I.F.McMurtry, K.R.Stenmark, P.A.Thistlethwaite, N.Weissmann, J.X.Yuan, and E.K.Weir (2009).
Cellular and molecular basis of pulmonary arterial hypertension.
  J Am Coll Cardiol, 54, S20-S31.  
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
17676627 A.Tsezou, M.Satra, P.Oikonomou, K.Bargiotas, and K.N.Malizos (2008).
The growth differentiation factor 5 (GDF5) core promoter polymorphism is not associated with knee osteoarthritis in the Greek population.
  J Orthop Res, 26, 136-140.  
19073914 C.Grütter, T.Wilkinson, R.Turner, S.Podichetty, D.Finch, M.McCourt, S.Loning, L.Jermutus, and M.G.Grütter (2008).
A cytokine-neutralizing antibody as a structural mimetic of 2 receptor interactions.
  Proc Natl Acad Sci U S A, 105, 20251-20256.
PDB codes: 3eo0 3eo1
18421531 P.Eliasson, A.Fahlgren, and P.Aspenberg (2008).
Mechanical load and BMP signaling during tendon repair: a role for follistatin?
  Clin Orthop Relat Res, 466, 1592-1597.  
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
17521337 A.Herpin, and C.Cunningham (2007).
Cross-talk between the bone morphogenetic protein pathway and other major signaling pathways results in tightly regulated cell-specific outcomes.
  FEBS J, 274, 2977-2985.  
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
16606344 C.Sieber, F.Plöger, R.Schwappacher, R.Bechtold, M.Hanke, S.Kawai, Y.Muraki, M.Katsuura, M.Kimura, M.M.Rechtman, Y.I.Henis, J.Pohl, and P.Knaus (2006).
Monomeric and dimeric GDF-5 show equal type I receptor binding and oligomerization capability and have the same biological activity.
  Biol Chem, 387, 451-460.  
16672363 G.P.Allendorph, W.W.Vale, and S.Choe (2006).
Structure of the ternary signaling complex of a TGF-beta superfamily member.
  Proc Natl Acad Sci U S A, 103, 7643-7648.
PDB code: 2goo
16640778 M.Kraich, M.Klein, E.Patiño, H.Harrer, J.Nickel, W.Sebald, and T.D.Mueller (2006).
A modular interface of IL-4 allows for scalable affinity without affecting specificity for the IL-4 receptor.
  BMC Biol, 4, 13.
PDB codes: 2b8u 2b8x 2b8y 2b8z 2b90 2b91 2d48
17125150 R.L.Rich, and D.G.Myszka (2006).
Survey of the year 2005 commercial optical biosensor literature.
  J Mol Recognit, 19, 478-534.  
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.