Crystal Structure of the Complex of Diphtheria Toxin with an Extracellular Fragment of Its Receptor

Abstract

We describe the crystal structure at 2.65 Å resolution of diphtheria toxin (DT) complexed 1:1 with a fragment of its cell-surface receptor, the precursor of heparin-binding epidermal-growth-factor-like growth factor (HBEGF). HBEGF in the complex has the typical EGF-like fold and packs its principal β hairpin against the face of a β sheet in the receptor-binding domain of DT. The interface has a predominantly hydrophobic core, and polar interactions are formed at the periphery. The structure of the complex suggests that part of the membrane anchor of the receptor can interact with a hinge region of DT. The toxin molecule is thereby induced to form an open conformation conducive to membrane insertion. The structure provides a basis for altering the binding specificity of the toxin, and may also serve as a model for other EGF–receptor interactions.