PDBsum entry 3eo1

Immune system/cytokine

PDB id: 3eo1

Contents

Protein chains

215 a.a. *

216 a.a. *

112 a.a. *

* Residue conservation analysis

PDB id:

3eo1

Name:

Immune system/cytokine

Title:

Structure of the fab fragment of gc-1008 in complex with transforming growth factor-beta 3

Structure:

Gc-1008 fab light chain. Chain: a, d, g, j. Engineered: yes. Gc-1008 fab heavy chain. Chain: b, e, h, k. Engineered: yes. Transforming growth factor beta-3. Chain: c, f, i, l. Fragment: unp residues 301-412, receptor binding fragment.

Source:

Mus musculus. Organism_taxid: 10090. Expressed in: mus musculus. Expression_system_taxid: 10090. Homo sapiens. Human. Organism_taxid: 9606. Gene: tgfb3. Expressed in: escherichia coli.

Resolution:

3.10Å R-factor: 0.255 R-free: 0.279

Authors:

C.Gruetter,M.G.Gruetter

Key ref:

C.Grütter et al. (2008). A cytokine-neutralizing antibody as a structural mimetic of 2 receptor interactions. Proc Natl Acad Sci U S A, 105, 20251-20256. PubMed id: 19073914 DOI: 10.1073/pnas.0807200106

Date:

26-Sep-08 Release date: 02-Dec-08

Protein chains

No UniProt id for this chain

Struc: 215 a.a.

Protein chains

P01861  (IGHG4_HUMAN) -  Immunoglobulin heavy constant gamma 4 from Homo sapiens

Seq: 396 a.a.

Struc: 216 a.a.

Protein chains

P10600  (TGFB3_HUMAN) -  Transforming growth factor beta-3 proprotein from Homo sapiens

Seq: 412 a.a.

Struc: 112 a.a.

DOI no: 10.1073/pnas.0807200106

Proc Natl Acad Sci U S A 105:20251-20256 (2008)

PubMed id: 19073914

A cytokine-neutralizing antibody as a structural mimetic of 2 receptor interactions.

C.Grütter, T.Wilkinson, R.Turner, S.Podichetty, D.Finch, M.McCourt, S.Loning, L.Jermutus, M.G.Grütter.

ABSTRACT

TGF-beta isoforms are key modulators of a broad range of biological pathways and increasingly are exploited as therapeutic targets. Here, we describe the crystal structures of a pan-TGF-beta neutralizing antibody, GC-1008, alone and in complex with TGF-beta3. The antibody is currently in clinical evaluation for idiopathic pulmonary fibrosis, melanoma, and renal cell cancer. GC-1008 recognizes an asymmetric binding interface across the TGF-beta homodimer with high affinity. Whereas both cognate receptors, TGF-beta-receptor types I and II, are required to recognize all 3 TGF-beta isoforms, GC-1008 has been engineered to bind with high affinity to TGF-beta1, 2, and 3 via a single interaction surface. Comparison with existing structures and models of TGF-beta interaction with its receptors suggests that the antibody binds to a similar epitope to the 2 receptors together and is therefore a structurally different but functionally identical mimic of the binding mode of both receptors.

Selected figure(s)

Figure 2.
GC-1008–TGF-β3 binding interface. (A) Surface representation of the complex. The main binding interactions of the Fab fragments toward the TGF-β3 homodimer are accomplished by CDR loops of the heavy chains (yellow). (B) Contact residues of GC-1008 (gray) involved in the recognition of TGF-β3. The TGF-β3 homodimer is shown as transparent surface representation.

Figure 4.
Comparison of the GC-1008 binding mode with type I and type II TGF-β receptor binding. (A) Structure of the ternary TGF-β signaling complex consisting of TGF-β3 bound to its type I and II receptors. Structure is shown as depicted in ref. 14. (B) Schematic comparison of GC-1008 binding versus receptor binding.

Figures were selected by an automated process.