The interferon-inducible p200 (IFI-200/HIN-200) family of proteins regulates cell growth and differentiation, and confers resistance to the development of tumors and virus infections. IFI-200 family members are thought to exert their biological effects by modulation of the transcriptional activities of numerous factors and interaction with other proteins through the C-terminal HIN domains. However, the HIN domain structure and function have remained obscure. Therefore, we performed a comprehensive bio-informatics analysis and assembled a structure-based multiple sequence alignment of IFI-200 proteins. The application of fold recognition methods revealed that the HIN domain consists of two consecutive OB domains. Our structural models of DNA-binding HIN domains afford the long-sought interpretations for many previous experimental observations. Our results also raise the possibility of as yet unexplored functional roles of IFI-200 proteins as transcriptional regulators and as interaction partners of proteins involved in immunomodulatory and apoptotic processes. (C) 2004 Elsevier Inc. All rights reserved.