PDBsum entry: 1dqt

Immune system

PDB id: 1dqt

Contents

Protein chains

117 a.a. *

Ligands

EDO

Metals

_CL ×4

Waters ×432

* Residue conservation analysis

PDB id:

1dqt

Name:

Immune system

Title:

The crystal structure of murine ctla4 (cd152)

Structure:

Cytotoxic t lymphocyte associated antigen 4. Chain: a, b, c, d. Fragment: extracellular fragment. Synonym: ctla4. Engineered: yes

Source:

Mus musculus. House mouse. Organism_taxid: 10090. Expressed in: escherichia coli. Expression_system_taxid: 562.

Biol. unit:

Dimer (from PQS)

Resolution:

2.00Å R-factor: 0.211 R-free: 0.254

Authors:

D.A.Ostrov,W.Shi,J.C.Schwartz,S.C.Almo,S.G.Nathenson

Key ref:

D.A.Ostrov et al. (2000). Structure of murine CTLA-4 and its role in modulating T cell responsiveness. Science, 290, 816-819. PubMed id: 11052947 DOI: 10.1126/science.290.5492.816

Date:

05-Jan-00 Release date: 27-Oct-00

Protein chains

P09793  (CTLA4_MOUSE) -  Cytotoxic T-lymphocyte protein 4

Seq: 223 a.a.

Struc: 117 a.a.

 Gene Ontology (GO) functional annotation 

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

DOI no: 10.1126/science.290.5492.816

Science 290:816-819 (2000)

PubMed id: 11052947

Structure of murine CTLA-4 and its role in modulating T cell responsiveness.

D.A.Ostrov, W.Shi, J.C.Schwartz, S.C.Almo, S.G.Nathenson.

ABSTRACT

The effective regulation of T cell responses is dependent on opposing signals transmitted through two related cell-surface receptors, CD28 and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4). Dimerization of CTLA-4 is required for the formation of high-avidity complexes with B7 ligands and for transmission of signals that attenuate T cell activation. We determined the crystal structure of the extracellular portion of CTLA-4 to 2.0 angstrom resolution. CTLA-4 belongs to the immunoglobulin superfamily and displays a strand topology similar to Valpha domains, with an unusual mode of dimerization that places the B7 binding sites distal to the dimerization interface. This organization allows each CTLA-4 dimer to bind two bivalent B7 molecules and suggests that a periodic arrangement of these components within the immunological synapse may contribute to the regulation of T cell responsiveness.

Selected figure(s)

Figure 1.
Fig. 1. Structure of CTLA-4. (A) On the right, ribbon diagram of the CTLA-4 monomer. The strands are labeled: A (3 to 6), A' (7 to 11), B (16 to 24), C (30 to 39), C' (43 to 53), C" (56 to 59), D (65 to 70), E (74 to 80), F (87 to 99), and G (103 to 114). The A'GFCC' (front) and ABEDC" (back) sheets are shown in gold and blue, respectively. Intersheet disulfide bonds between the B and F strands and between the C' and D strands are shown in yellow. Inset on the top left shows the strand topology for typical v-type immunoglobulin domains (e.g., V[H], V[L], V ). Inset on the bottom left shows the strand topology for V domains and CTLA-4 in which the C" strand is part of the back sheet. (B) Ribbon diagram of the CTLA-4 dimer. The CTLA-4 homodimer is oriented with the molecular diad axis situated vertically in the plane of the page. In this orientation, the COOH-termini extend from the bottom of the molecule. The dimer interface is formed primarily by the ABEDC" (back) sheets, shown in blue. The CDR analogous regions, CDR1 (BC loop), CDR2 (C'C" loop), and CDR3 (FG loop), form the top surface of the molecule. The distance between the CDR3 analogous regions in the dimer is 47 Å. (C) Detailed view of the CTLA-4 dimer interface. The twofold axis of the dimer is perpendicular to the page. The backbones of the CTLA-4 monomers are shown in green and in sky blue. The side chains involved in hydrogen bonding and van der Waals interactions at the dimer interface are displayed (23), with C, O, and N atoms depicted in yellow, red, and blue, respectively. Figure 1 was made with the program SETOR (41).

Figure 3.
Fig. 3. B7 binding sites on CTLA-4 and placement of CDR3 regions in dimers of immunoglobulin domains. The molecular surfaces of the TCR V V heterodimer (1tcr) and the CTLA-4 homodimer (1dqt) are shown in (A) and (B), respectively, with the CTLA-4 twofold axis oriented perpendicular to the page. Because of front-to-front packing in the TCR, the CDR3 regions shown in red are juxtaposed at the dimer interface (A), whereas the back-to-back packing present in CTLA-4 positions the CDR3 regions distal to the dimer interface (B). The two B7 binding sites on the CTLA-4 homodimer, as mapped by mutagenesis (26), include the FG loop (CDR3) shown in red, the BC loop (CDR1) shown in yellow, and solvent-accessible residues on the A'GFCC' sheet (Glu31, Arg33, Glu46, Lys93, Glu95, Phe^103, and Val104), shown in yellow (18). In contrast to V V and Fab, which are monovalent for their respective ligands (i.e., peptide-MHC complex and antigen), the placement of ligand binding sites at the extremes of the CTLA-4 dimer suggests that each CTLA-4 monomer may interact with an individual B7 dimer. (A) and (B) were prepared with GRASP (45). (C) Model of organized interactions between CTLA-4 and B7 dimers in the immunological synapse. CTLA-4 dimers, shown in red, are depicted with their COOH-termini modeled to include the disulfide bond at Cys120 near the T cell plasma membrane. CTLA-4 was manually docked to B7-1 d1, shown in light blue, to maximize the interaction between residues implicated by site-directed mutagenesis, in particular, CDR3 (Met97TyrProProProTyr102) of CTLA-4, and a hydrophobic patch on the A'GFCC'C" face of B7-1 (25). Each CTLA-4 dimer is depicted as binding two independent B7 dimers with an intermolecular spacing of approximately 77 Å and an intermembrane distance spanned by the CTLA-4-B7 ligand pair of approximately 100 Å. (C) was made with the program SETOR (41).

The above figures are reprinted by permission from the AAAs: Science (2000, 290, 816-819) copyright 2000.

Figures were selected by an automated process.