PDBsum entry: 1i85

Immune system

PDB id: 1i85

Contents

Protein chains

110 a.a. *

118 a.a. *

111 a.a. *

* Residue conservation analysis

PDB id:

1i85

Name:

Immune system

Title:

Crystal structure of the ctla-4/b7-2 complex

Structure:

T lymphocyte activation antigen cd86. Chain: a, b. Fragment: ig v-type (receptor binding) domain. Synonym: b7-2. Engineered: yes. Cytotoxic t-lymphocyte-associated protein 4. Chain: c, d. Fragment: extracellular domain. Synonym: ctla-4.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: cd86. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008. Gene: ctla4.

Biol. unit:

Tetramer (from PQS)

Resolution:

3.20Å R-factor: 0.217 R-free: 0.300

Authors:

J.-C.D.Schwartz,X.Zhang,A.A.Fedorov,S.G.Nathenson,S.C.Almo

Key ref:

J.C.Schwartz et al. (2001). Structural basis for co-stimulation by the human CTLA-4/B7-2 complex. Nature, 410, 604-608. PubMed id: 11279501 DOI: 10.1038/35069112

Date:

12-Mar-01 Release date: 04-Apr-01

Protein chains

P42081  (CD86_HUMAN) -  T-lymphocyte activation antigen CD86

Seq: 329 a.a.

Struc: 110 a.a.*

Protein chain

P16410  (CTLA4_HUMAN) -  Cytotoxic T-lymphocyte protein 4

Seq: 223 a.a.

Struc: 118 a.a.

Protein chain

P16410  (CTLA4_HUMAN) -  Cytotoxic T-lymphocyte protein 4

Seq: 223 a.a.

Struc: 111 a.a.

* PDB and UniProt seqs differ at 1 residue position (black cross)

 Gene Ontology (GO) functional annotation 

• Cellular component: membrane (1 term)
• Biological process: immune response (1 term)

DOI no: 10.1038/35069112

Nature 410:604-608 (2001)

PubMed id: 11279501

Structural basis for co-stimulation by the human CTLA-4/B7-2 complex.

J.C.Schwartz, X.Zhang, A.A.Fedorov, S.G.Nathenson, S.C.Almo.

ABSTRACT

Regulation of T-cell activity is dependent on antigen-independent co-stimulatory signals provided by the disulphide-linked homodimeric T-cell surface receptors, CD28 and CTLA-4 (ref. 1). Engagement of CD28 with B7-1 and B7-2 ligands on antigen-presenting cells (APCs) provides a stimulatory signal for T-cell activation, whereas subsequent engagement of CTLA-4 with these same ligands results in attenuation of the response. Given their central function in immune modulation, CTLA-4- and CD28-associated signalling pathways are primary therapeutic targets for preventing autoimmune disease, graft versus host disease, graft rejection and promoting tumour immunity. However, little is known about the cell-surface organization of these receptor/ligand complexes and the structural basis for signal transduction. Here we report the 3.2-A resolution structure of the complex between the disulphide-linked homodimer of human CTLA-4 and the receptor-binding domain of human B7-2. The unusual dimerization properties of both CTLA-4 and B7-2 place their respective ligand-binding sites distal to the dimer interface in each molecule and promote the formation of an alternating arrangement of bivalent CTLA-4 and B7-2 dimers that extends throughout the crystal. Direct observation of this CTLA-4/B7-2 network provides a model for the periodic organization of these molecules within the immunological synapse and suggests a distinct mechanism for signalling by dimeric cell-surface receptors.

Selected figure(s)

Figure 1.
Figure 1: The CTLA-4/B7-2-binding interface. a, Ribbon diagram of the CTLA-4/B7-2 monomers that form the binding interface. For CTLA-4, the strands are labelled A (residues 4 -8), A' (residues 11 -13), B (residues19 -26), C (residues 33 -42), C' (residues 45 -54), C" (residues 56 -60), D (residues 67 -72), E (residues 75 -81), F (residues 90 -99) and G (residues 105 -109; 112 -115). The A'GFCC' (front) and ABEDC" (back) sheets are coloured pink and red, respectively. The CDR3-like loop of CTLA-4 is labelled. For B7-2, the strands are labelled A (residues 3 -7), B (residues 9 -11), C (residues 27 -35), C' (residues 38 -45), C" (residues 47 -49), D (residues 60 -64), E (residues 67 -73), F (residues 81 -91) and G (residues 94 -108). The AGFCC'C" (front) and BED (back) sheets are coloured dark blue and blue, respectively. All inter-sheet disulphides are shown in yellow. b, Detailed view of the human CTLA-4/B7-2 interface. The interface is formed by residues from the front sheets of CTLA-4 (CDR3 and the C and C' strands) and a concave surface on B7-2 (the G, F, C, C' and C" strands and the CC', C"D and FG loops).

Figure 2.
Figure 2: The disulphide-linked human CTLA-4 dimer. a, Ribbon diagram of the CTLA-4 dimer. The interface has contributions from residues C-terminal to the G strand and centred around the A' strand. The CDR analogous regions (CDR1, CDR2 and CDR3) are labelled and potential glycosylation sites are highlighted in green. The observed organization places the B7-binding sites distal to the dimer interface. b, Detailed view of the CTLA-4 dimer interface. This same interface is also present in the unliganded human CTLA-4 disulphide-linked dimer (J.-C.D.S. and X.Z., unpublished results). c, Sequence alignment of the CTLA-4/CD28 family. Residues that participate in the human CTLA-4 dimer interface (filled circle) and B7-2-binding site (asterisk) are indicated. Residues with greater than 50% conservation are coloured in yellow, whereas those that are invariant are red. The residues in the human CTLA-4 dimer interface are coloured in blue, whereas the analogous residues in CD28 are green. H, human; m, murine; rt, rat; rb, rabbit. Strand colours are the same as in Fig. 1.

The above figures are reprinted by permission from Macmillan Publishers Ltd: Nature (2001, 410, 604-608) copyright 2001.

Figures were selected by the author.