PDBsum entry 2dsq

Protein binding/hormone/growth factor

PDB id: 2dsq

Contents

Protein chains

87 a.a. *

49 a.a. *

51 a.a. *

73 a.a. *

58 a.a. *

* Residue conservation analysis

PDB id:

2dsq

Name:

Protein binding/hormone/growth factor

Title:

Structural basis for the inhibition of insulin-like growth factors by igf binding proteins

Structure:

Insulin-like growth factor-binding protein 4. Chain: b, a. Fragment: n-terminal domain. Synonym: igfbp-4, ibp-4, igf-binding protein 4. Engineered: yes. Insulin-like growth factor ib. Chain: i, c. Synonym: igf-ib, somatomedin c, mechano growth factor, mgf. Engineered: yes.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.

Biol. unit:

Hexamer (from PQS)

Resolution:

2.80Å R-factor: 0.292 R-free: 0.357

Authors:

T.Sitar,G.M.Popowicz,I.Siwanowicz,R.Huber,T.A.Holak

Key ref:

T.Sitar et al. (2006). Structural basis for the inhibition of insulin-like growth factors by insulin-like growth factor-binding proteins. Proc Natl Acad Sci U S A, 103, 13028-13033. PubMed id: 16924115 DOI: 10.1073/pnas.0605652103

Date:

05-Jul-06 Release date: 22-Aug-06

Protein chains

P22692  (IBP4_HUMAN) -  Insulin-like growth factor-binding protein 4 from Homo sapiens

Seq: 258 a.a.

Struc: 87 a.a.

Protein chain

Q9NP10  (Q9NP10_HUMAN) -  Insulin-like growth factor I from Homo sapiens

Seq: 130 a.a.

Struc: 49 a.a.

Protein chain

Q9NP10  (Q9NP10_HUMAN) -  Insulin-like growth factor I from Homo sapiens

Seq: 130 a.a.

Struc: 51 a.a.

Protein chain

P08833  (IBP1_HUMAN) -  Insulin-like growth factor-binding protein 1 from Homo sapiens

Seq: 259 a.a.

Struc: 73 a.a.

Protein chain

P08833  (IBP1_HUMAN) -  Insulin-like growth factor-binding protein 1 from Homo sapiens

Seq: 259 a.a.

Struc: 58 a.a.

DOI no: 10.1073/pnas.0605652103

Proc Natl Acad Sci U S A 103:13028-13033 (2006)

PubMed id: 16924115

Structural basis for the inhibition of insulin-like growth factors by insulin-like growth factor-binding proteins.

T.Sitar, G.M.Popowicz, I.Siwanowicz, R.Huber, T.A.Holak.

ABSTRACT

Insulin-like growth factor-binding proteins (IGFBPs) control bioavailability, activity, and distribution of insulin-like growth factor (IGF)1 and -2 through high-affinity IGFBP/IGF complexes. IGF-binding sites are found on N- and C-terminal fragments of IGFBPs, the two conserved domains of IGFBPs. The relative contributions of these domains to IGFBP/IGF complexation has been difficult to analyze, in part, because of the lack of appropriate three-dimensional structures. To analyze the effects of N- and C-terminal domain interactions, we determined several x-ray structures: first, of a ternary complex of N- and C-terminal domain fragments of IGFBP4 and IGF1 and second, of a "hybrid" ternary complex using the C-terminal domain fragment of IGFBP1 instead of IGFBP4. We also solved the binary complex of the N-terminal domains of IGFBP4 and IGF1, again to analyze C- and N-terminal domain interactions by comparison with the ternary complexes. The structures reveal the mechanisms of IGF signaling regulation via IGFBP binding. This finding supports research into the design of IGFBP variants as therapeutic IGF inhibitors for diseases of IGF disregulation. In IGFBP4, residues 1-38 form a rigid disulphide bond ladder-like structure, and the first five N-terminal residues bind to IGF and partially mask IGF residues responsible for the type 1 IGF receptor binding. A high-affinity IGF1-binding site is located in a globular structure between residues 39 and 82. Although the C-terminal domains do not form stable binary complexes with either IGF1 or the N-terminal domain of IGFBP4, in the ternary complex, the C-terminal domain contacts both and contributes to blocking of the IGF1 receptor-binding region of IGF1.

Selected figure(s)

Figure 3.
Fig. 3. The interaction of IGF1 (green) with NBP4 (residues 3–82) (the yellow surface) and CBP4 (residues 151–232) (the blue surface). Residues discussed in Results and Discussion are labeled and shown in stick representation; two hydrogen bonds from the thumb to IGF1and CBP4 are also shown.

Figure 4.
Fig. 4. Interaction of the thumb region of NBP4 (residues 3–82) (dark red) and NBP4 (residues 1–92) (dark blue) complexed to IGF1; IGF1s are in green, with the residues important for the IGF–IR binding labeled.

Figures were selected by an automated process.