Crystal Structure at 2.8 Å of an FcRn/Heterodimeric Fc Complex: Mechanism of pH-Dependent Binding
Abstract
The neonatal Fc receptor (FcRn) transports immunoglobulin G (IgG) across epithelia, binding IgG in acidic vesicles (pH ≤ 6.5) and releasing IgG in the blood at pH 7.4. Well-ordered FcRn/Fc crystals are prevented by the formation of "oligomeric ribbons" of FcRn dimers bridged by Fc homodimers, thus we crystallized a 1:1 complex between rat FcRn and a heterodimeric Fc containing only one FcRn binding site. The 2.8 Å complex structure demonstrates that FcRn uses its α2 and β2-microglobulin domains and carbohydrate to interact with the Fc C_γ2–C_γ3 interface. The structure reveals conformational changes in Fc and three titratable salt bridges that confer pH-dependent binding, and can be used to guide rational design of therapeutic IgGs with longer serum half-lives.
Additional Information
© 2001 Cell Press. Received 6 December 2000, Revised 16 February 2001, Available online 4 May 2001. This work was supported by a grant from the NIH (AI/GM41239 to P. J. B.), a Caltech Biology Division Ferguson predoctoral fellowship (BIO.41783-1-ENDOW.471830 to W. L. M.), and a Damon Runyon Walter Winchell Foundation Fellowship (DRG-1445 to A. P. W.). We thank Mark Ultsch for Fc coordinates; Warren DeLano, Loredana Lo Conte, and BenBornstein for helpful discussions about computations; and Melanie Bennett, Andrew Herr, Christopher O'Callaghan, T. S. Ramalingam, and Anthony West for critical reading of the manuscript.Additional details
- Eprint ID
- 75436
- DOI
- 10.1016/S1097-2765(01)00230-1
- Resolver ID
- CaltechAUTHORS:20170327-143505044
- AI/GM41239
- NIH
- BIO.41783-1-ENDOW.471830
- Caltech Division of Biology Ferguson Fellowship
- DRG-1445
- Damon Runyon-Walter Winchell Foundation Cancer Research Fund
- Created
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2017-03-28Created from EPrint's datestamp field
- Updated
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2021-11-15Created from EPrint's last_modified field