Structural basis for binding of human IgG1 to its high-affinity human receptor FcγRI

Masato Kiyoshi, Jose M.M. Caaveiro (), Takeaki Kawai, Shinya Tashiro, Teruhiko Ide, Yoshiharu Asaoka, Kouta Hatayama and Kouhei Tsumoto ()
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Masato Kiyoshi: Graduate School of Engineering, The University of Tokyo
Jose M.M. Caaveiro: Graduate School of Engineering, The University of Tokyo
Takeaki Kawai: Graduate School of Frontier Sciences, The University of Tokyo
Shinya Tashiro: Graduate School of Frontier Sciences, The University of Tokyo
Teruhiko Ide: Tosoh Corporation, Hayakawa
Yoshiharu Asaoka: Tosoh Corporation, Hayakawa
Kouta Hatayama: Sagami Chemical Research Institute, Hayakawa
Kouhei Tsumoto: Graduate School of Engineering, The University of Tokyo

Nature Communications, 2015, vol. 6, issue 1, 1-11

Abstract: Abstract Cell-surface Fcγ receptors mediate innate and adaptive immune responses. Human Fcγ receptor I (hFcγRI) binds IgGs with high affinity and is the only Fcγ receptor that can effectively capture monomeric IgGs. However, the molecular basis of hFcγRI’s interaction with Fc has not been determined, limiting our understanding of this major immune receptor. Here we report the crystal structure of a complex between hFcγRI and human Fc, at 1.80 Å resolution, revealing an unique hydrophobic pocket at the surface of hFcγRI perfectly suited for residue Leu235 of Fc, which explains the high affinity of this complex. Structural, kinetic and thermodynamic data demonstrate that the binding mechanism is governed by a combination of non-covalent interactions, bridging water molecules and the dynamic features of Fc. In addition, the hinge region of hFcγRI-bound Fc adopts a straight conformation, potentially orienting the Fab moiety. These findings will stimulate the development of novel therapeutic strategies involving hFcγRI.

Date: 2015
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DOI: 10.1038/ncomms7866

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