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Crystal Structure at 2.8 Å of an FcRn/Heterodimeric Fc Complex: Mechanism of pH-Dependent Binding

Martin, W. Lance and West, Anthony P., Jr. and Gan, Lu and Bjorkman, Pamela J. (2001) Crystal Structure at 2.8 Å of an FcRn/Heterodimeric Fc Complex: Mechanism of pH-Dependent Binding. Molecular Cell, 7 (4). pp. 867-877. ISSN 1097-2765. https://resolver.caltech.edu/CaltechAUTHORS:20170327-143505044

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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.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1016/S1097-2765(01)00230-1DOIArticle
http://www.sciencedirect.com/science/article/pii/S1097276501002301PublisherArticle
ORCID:
AuthorORCID
Gan, Lu0000-0002-8685-4896
Bjorkman, Pamela J.0000-0002-2277-3990
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.
Funders:
Funding AgencyGrant Number
NIHAI/GM41239
Caltech Division of Biology Ferguson FellowshipBIO.41783-1-ENDOW.471830
Damon Runyon-Walter Winchell Foundation Cancer Research FundDRG-1445
Issue or Number:4
Record Number:CaltechAUTHORS:20170327-143505044
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20170327-143505044
Official Citation:W.Lance Martin, Anthony P West Jr., Lu Gan, Pamela J Bjorkman, Crystal Structure at 2.8 Å of an FcRn/Heterodimeric Fc Complex: Mechanism of pH-Dependent Binding, Molecular Cell, Volume 7, Issue 4, April 2001, Pages 867-877, ISSN 1097-2765, http://dx.doi.org/10.1016/S1097-2765(01)00230-1. (http://www.sciencedirect.com/science/article/pii/S1097276501002301)
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:75436
Collection:CaltechAUTHORS
Deposited By: Ruth Sustaita
Deposited On:28 Mar 2017 16:56
Last Modified:05 Nov 2019 21:12

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