Crystal structure of the B7-1/CTLA-4 complex that inhibits human immune responses

Stamper CC, Zhang Y, Tobin JF, Erbe DV, Ikemizu S, Davis SJ, Stahl ML, Seehra J, Somers WS, Mosyak L. (2001), Nature. 410, 608-11

Abstract

Optimal immune responses require both an antigen-specific and a co-stimulatory signal. The shared ligands B7-1 and B7-2 on antigen-presenting cells deliver the co-stimulatory signal through CD28 and CTLA-4 on T cells. Signalling through CD28 augments the T-cell response, whereas CTLA-4 signalling attenuates it. Numerous animal studies and recent clinical trials indicate that manipulating these interactions holds considerable promise for immunotherapy. With the consequences of these signals well established, and details of the downstream signalling events emerging, understanding the molecular nature of these extracellular interactions becomes crucial. Here we report the crystal structure of the human CTLA-4/B7-1 co-stimulatory complex at 3.0 Å resolution. In contrast to other interacting cell-surface molecules, the relatively small CTLA-4/B7-1 binding interface exhibits an unusually high degree of shape complementarity. CTLA-4 forms homodimers through a newly defined interface of highly conserved residues. In the crystal lattice, CTLA-4 and B7-1 pack in a strikingly periodic arrangement in which bivalent CTLA-4 homodimers bridge bivalent B7-1 homodimers. This zipper-like oligomerization provides the structural basis for forming unusually stable signalling complexes at the T-cell surface, underscoring the importance of potent inhibitory signalling in human immune responses.

Key figure: Overview of receptor–ligand interactions

a, Ribbon diagram showing orthogonal interaction between sCTLA-4 (cyan) and sB7-1 (purple) monomers. Also shown is the molecular surface representation (white transparent) of the ligand-binding domain of sB7-1 to emphasize the high geometric match between the two interacting surfaces. b, Direct receptor–ligand contacts. The ⁹⁹MYPPPY¹⁰⁴ loop of sCTLA-4 is buried in a shallow depression of the sB7-1 GFCC’ surface. Colour coding is as in a. Three out of five hydrogen bonds formed across the β-sheets of the interacting domains are depicted as red dashed lines. Several other side chains on CTLA-4 and B7-1 (not shown) may contribute to the binding through appreciable, but not direct, contacts formed on the periphery of the binding interface. Figure prepared with BobScript³⁰.

Key figure: Molecular association of sCTLA-4 and sB7-1 in the crystal lattice

Shown are ‘skewed zipper’ arrays in which sCTLA-4/sB7-1 complexes would be evenly spaced along membrane surfaces with a separation of 105 Å. In the perpendicular direction, across membranes, ligated receptors would span 140 Å. Geometrically, sugar chains attached at Asn 173 on B7-1 (bottom) are close to the cell membrane, implying their potential involvement in interaction with the membrane, perhaps by stabilizing the orientation of the B7-1 dimers. APC, antigen-presenting cell. Figure prepared with RIBBONS²⁹.