ABSTRACTAnkyrins (Ank) are a ubiquitously expressed family of multifunctional membrane adapter proteins. Ankyrin G (AnkG) is critical for assembling and maintenance of the axon initial segment. Here we present the 2.1 Å crystal structure of human AnkG death domain (hAnkG‐DD). The core death domain is composed of six α‐helices and three 310‐helices. It forms a hydrophobic pocket on the surface of the molecule. The C‐terminal tail of the hAnkG‐DD curves back to have the aromatic ring of a phenylalanine residue, Phe100 insert into this pocket, which anchors the flexible tail onto the core domain. Related DDs were selected for structure comparison. The major variations are at the C‐terminal region, including the α6 and the long C‐terminal extension. The results of size exclusion chromatography and analytical ultracentrifugation suggest that hAnkG‐DD exists as monomer in solution. Our work should help for the future investigation of the structure–function of AnkG. Proteins 2014; 82:3476–3482. © 2014 Wiley Periodicals, Inc.