PDBsum entry: 1waq

Growth factor

PDB id: 1waq

Contents

Protein chain

104 a.a. *

Ligands

MPD ×3

Waters ×23

* Residue conservation analysis

PDB id:

1waq

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)

Resolution:

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

Date:

27-Oct-04 Release date: 19-May-05

Protein chain

P43026  (GDF5_HUMAN) -  Growth/differentiation factor 5

Seq: 501 a.a.

Struc: 104 a.a.

 Gene Ontology (GO) functional annotation 

• 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.

ABSTRACT

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.