Structural basis for binding of human IgG1 to its high-affinity human receptor FcγRI.
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.
Department of Bioengineering, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Tokyo 113-8656, Japan.
Masato
M
Kiyoshi
Department of Bioengineering, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Tokyo 113-8656, Japan.
Jose M M
JM
Caaveiro
Department of Medical Genome Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa 277-8562, Japan.
Takeaki
T
Kawai
Department of Medical Genome Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa 277-8562, Japan.
Shinya
S
Tashiro
1] Tosoh Corporation, Hayakawa, Ayase 252-1123, Japan [2] Sagami Chemical Research Institute, Hayakawa, Ayase 252-1193, Japan.
Teruhiko
T
Ide
Tosoh Corporation, Hayakawa, Ayase 252-1123, Japan.
Yoshiharu
Y
Asaoka
Sagami Chemical Research Institute, Hayakawa, Ayase 252-1193, Japan.
Kouta
K
Hatayama
1] Department of Bioengineering, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Tokyo 113-8656, Japan [2] Department of Medical Genome Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa 277-8562, Japan [3] Laboratory of Medical Proteomics, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
Kouhei
K
Tsumoto
D000595:Amino Acid Sequence; D006801:Humans; D007074:Immunoglobulin G / Q000737:chemistry* / Q000378:metabolism; D008969:Molecular Sequence Data; D011487:Protein Conformation; D017452:Receptors, IgG / Q000737:chemistry* / Q000378:metabolism; D020349:Surface Plasmon Resonance
C489017:FCGR1A protein, human; D007074:Immunoglobulin G; D017452:Receptors, IgG