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Published September 18, 1998 | public
Journal Article

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

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.

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.).

Additional details

Created:
August 22, 2023
Modified:
October 25, 2023