Three-dimensional structure of an angiotensin II-Fab complex at 3 A: hormone recognition by an anti-idiotypic antibody.
The elucidation of bioactive conformations of small peptide hormones remains an elusive goal to structural chemists because of the inherent flexibility of these molecules. Angiotensin II (AII), the major effector of the renin-angiotensin system, is an octapeptide hormone for which no clear structural models exist. Peptide hormones such as AII share the property that they bind to their receptors with high affinities, in spite of the fact that they must overcome an extremely large conformational entropy barrier to bind in one conformation. A "surrogate system" that consists of a high-affinity monoclonal antibody (MAb) and AII has been used to study a bound conformation of AII. The crystallographic structure of the complex reveals a structure of AII that is compatible with predicted bioactive conformations of AII derived from structure-activity studies and theoretical calculations. In the complex, the deeply bound hormone is folded into a compact structure in which two turns bring the amino and carboxyl termini close together. The antibody of this complex (MAb 131) has the unusual property that it was not generated against AII, but rather against an anti-idiotypic antibody reactive with a MAb to AII, which renders this antibody an anti-anti-idiotypic antibody. The high affinity for AII of the original MAb to AII was passed on to MAb 131 through a structural determinant on the anti-idiotypic antibody. Strikingly, the conformation of AII in this complex is highly similar to complementarity determining region loops of antibodies, possibly indicating that a true molecular mimic of bound AII was present on the anti-idiotypic antibody against which MAb 131 was elicited.
Garcia
K C
KC
Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
Ronco
P M
PM
Verroust
P J
PJ
Brünger
A T
AT
Amzel
L M
LM
D000595:Amino Acid Sequence; D000804:Angiotensin II / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism; D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000737:chemistry* / Q000378:metabolism; D000911:Antibodies, Monoclonal / Q000737:chemistry* / Q000378:metabolism; D000936:Antigen-Antibody Complex; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011487:Protein Conformation; D014961:X-Ray Diffraction
D000888:Antibodies, Anti-Idiotypic; D000911:Antibodies, Monoclonal; D000936:Antigen-Antibody Complex; D007140:Immunoglobulin Fab Fragments; D000804:Angiotensin II