COMPUTATIONAL DETERMINATION OF THE STRUCTURE OF RAT FC BOUND TO THE NEONATAL FC RECEPTOR

The available crystal structure for the complex between the Fc fragmen t of immunoglobulin G (IgG) and the neonatal Fc receptor (FcRn) was de termined at low resolution and has no electron density for a large por tion of the C(H)2 domain of the Fc. Here, we use a well validated comp utational docking algorithm in conjunction with known crystallographic data to predict the orientation of CH2 when bound to FcRn, and valida te the predicted structure with data from site-specific mutagenesis ex periments. The predicted Fc structure indicates that the CH2 domain mo ves 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(H)2 domain is displaced by an average of 6 Angstrom from the C(H)2 orientation in the structu re of Fc alone, and shows improved charge complementarity with FcRn. T he predicted effects of 11 specific mutations in Fc and FcRn are calcu lated 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 curr ent study predicts that FcRn-bound Fc is asymmetric due to reorientati on of the C(H)2 domain upon FcRn binding, a rearrangement that would b e likely to interfere with optimal binding of FcRn at the second bindi ng site of the Fc homodimer. (C) 1998 Academic Press.