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Computational determination of the structure of rat Fc bound to the neonatal Fc receptor

Weng, Zhiping and Gulukota, Kamalakar and Vaughn, Daniel E. and Bjorkman, Pamela J. and DeLisi, Charles (1998) Computational determination of the structure of rat Fc bound to the neonatal Fc receptor. Journal of Molecular Biology, 282 (2). pp. 217-225. ISSN 0022-2836. doi:10.1006/jmbi.1998.2020. https://resolver.caltech.edu/CaltechAUTHORS:20170405-153514866

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Abstract

The available crystal structure for the complex between the Fc fragment of immunoglobulin G (IgG) and the neonatal Fc receptor (FcRn) was determined at low resolution and has no electron density for a large portion of the C_H2 domain of the Fc. Here, we use a well validated computational docking algorithm in conjunction with known crystallographic data to predict the orientation of C_H2 when bound to FcRn, and validate the predicted structure with data from site-specific mutagenesis experiments. The predicted Fc structure indicates that the C_H2 domain moves upon binding FcRn, such that the end-to-end distance of the bound Fc fragment is greater than it is in the crystal structure of isolated Fc. The calculated orientation of the bound C_H2 domain is displaced by an average of 6 Å from the C_H2 orientation in the structure of Fc alone, and shows improved charge complementarity with FcRn. The predicted effects of 11 specific mutations in Fc and FcRn are calculated and the results are compared with experimental measurements. The predicted structure is consistent with all reported mutagenesis data, some of which are explicable only on the basis of our model. The current study predicts that FcRn-bound Fc is asymmetric due to reorientation of the C_H2 domain upon FcRn binding, a rearrangement that would be likely to interfere with optimal binding of FcRn at the second binding site of the Fc homodimer.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1006/jmbi.1998.2020DOIArticle
http://www.sciencedirect.com/science/article/pii/S0022283698920204PublisherArticle
ORCID:
AuthorORCID
Bjorkman, Pamela J.0000-0002-2277-3990
Additional Information:© 1998 Academic Press. Received 23 February 1998, Revised 14 May 1998, Accepted 15 May 1998. This work was supported by NSF (DBI-9630188 to C.D., Z.W. and K.G.), DOE (DE-FG02-96ER62263.A000 to C.D., Z.W. and K.G.), NIH (AI/GM41239 to P.J.B.), and a Camille and Henry Dreyfuss Teacher Scholar Award (P.J.B.).
Funders:
Funding AgencyGrant Number
NSFDBI-9630188
Department of Energy (DOE)DE-FG02-96ER62263.A000
NIHAI/GM41239
Camille and Henry Dreyfus FoundationUNSPECIFIED
Subject Keywords:crystallographic symmetry breaking; domain rearrangement; empirical binding free energy; molecular docking
Issue or Number:2
DOI:10.1006/jmbi.1998.2020
Record Number:CaltechAUTHORS:20170405-153514866
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20170405-153514866
Official Citation:Zhiping Weng, Kamalakar Gulukota, Daniel E. Vaughn, Pamela J. Bjorkman, Charles DeLisi, Computational determination of the structure of rat fc bound to the neonatal fc receptor1, Journal of Molecular Biology, Volume 282, Issue 2, 18 September 1998, Pages 217-225, ISSN 0022-2836, http://dx.doi.org/10.1006/jmbi.1998.2020. (http://www.sciencedirect.com/science/article/pii/S0022283698920204)
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:75753
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:05 Apr 2017 22:50
Last Modified:15 Nov 2021 16:36

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