Structures of cell surface receptorligand complexes

The structures of several receptor-ligand complexes have also been reported (see Table 1). For immune cell surface receptors, ligand-induced receptor oligo-merization is a major determinant of signal transduction. Figure 3 compares the structures of the complexes involving human growth hormone (hGH) receptor (hGHR) and the 55 kDa tumor necrosis factor (TNF) receptor (TNFR).

The prototypic fold of the TNFR/nerve growth factor receptor superfamily (Figure 3A) consists of stacked elongated domains. These domains have a very limited hydrophobic core and are stabilized by conserved disulfide bonds in a ladder-like arrangement. TNFR includes four domains, but only domains 2 and 3, which contact ligand, are well ordered in the X-ray structure. In contrast, the TNF fold consists of an antiparallel 3 sandwich with jelly-roll topology. Three monomers form a threefold symmetrical trimer. Three symmetry-related recep-tor-binding sites are formed at the interfaces between the TNF monomers. The receptor binds roughly parallel to the threefold axis, and the bound receptors do not contact each other. Thus, ligand binding leads to TNFR trimerization. Structures of free TNF and TNFR have shown that neither ligand nor receptor undergo significant conformational changes upon binding. In the crystal of uncomplexed TNFR,

Figure 3 Cell surface receptor-ligand complexes. Structures are represented as backbone traces (receptors, thick lines; ligands, thin lines). (A) The TNFp/TNFR complex. From left to right: TNFR. a TNF subunit, trimeric TNF, and the TNF/TNFR complex. (B) hGH/hGHR. From left to right: hGHR, consisting of two FN type Ill-like domains (see also Figure 1). hGH, and the hGH/hGHR complex.

Figure 3 Cell surface receptor-ligand complexes. Structures are represented as backbone traces (receptors, thick lines; ligands, thin lines). (A) The TNFp/TNFR complex. From left to right: TNFR. a TNF subunit, trimeric TNF, and the TNF/TNFR complex. (B) hGH/hGHR. From left to right: hGHR, consisting of two FN type Ill-like domains (see also Figure 1). hGH, and the hGH/hGHR complex.

dimeric forms were observed which, if present on the cell surface, may stabilize an inactive state of TNFR in the absence of ligand.

Figure 3B shows the structure of the hGH/hGHR complex. The receptor consists of two FN type III domains, and the ligand displays a four helix bundle fold. The hGHR architecture is shared by other cytokine receptors including the human prolactin receptor (hPRLR), the interferon y receptor (IFNyRa) and tissue factor (TF), but the relative orientations of the FN type III domains differ. Binding of hGH to its receptor leads to receptor dimerization. In contrast to TNF/TNFR, the binding sites in the hGH/hGHR complex are not equivalent, and the bound receptors contact each other. The hGH/hGHR interaction is asymmetrical in the sense that the receptors bind to different sites of the ligand. The complex forms sequentially. First, a high affinity 1:1 complex is formed, then a second receptor is engaged in the interaction. The binding of the second receptor is stabilized by receptor-receptor interactions. hGH also binds to hPRLR, and the structure of a 1:1 (high-affinity) hGH/hPRLR complex has been determined. This interaction is made possible in part by changes in the relative domain orientation of hPRLR compared to hGHR.

The erythropoietin (EPO) receptor is also structurally similar to hGHR but dimerizes in a somewhat different orientation when complexed with an agonist peptide. In contrast to hGH, IFN-y is an intertwined helix bundle homodimer. Two equivalent receptor-binding sites are presented which correspond to the high-affinity site in hGH. In the structure of the complex, receptors are bound at twofold symmetry-related sites and are separated by -27 A. Tissue factor binds a structurally distinct ligand, blood coagulation factor VIIAa, in a 1:1 complex. The TF region involved in binding differs topological^ from the binding sites in hGHR. The interleukin (IL)-l receptor consists of three extracellular Ig-like domains and binds IL-ip (and an antagonist) involving regions not corresponding to those in other cytokine receptors.

The structure of the rat neonatal Fc receptor (NFcR), responsible for binding maternal IgG, is very similar to MHC class I. However, the helices corresponding to the MHC peptide-binding site move together and essentially close the groove. A low-res olution structure of NFcR in complex with an Fc fragment has shown that the Fc-binding site does not correspond to the MHC peptide-binding site. Rather, the Fc fragment binds to the side of the receptor. The NFcR/Fc complex provides an instructive example of how similar structures can mediate distinct binding functions.

See also: Adhesion molecules; Antigens, cell surface; CD antigens; Cytokine receptors; Domains, immuno-giobulin-type; Immunoglobulin gene superfamily; Specificity; Antibody-antigen complexes, three-dimensional structures.

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