Structural Unity among Viral Origin Binding Proteins: Crystal Structure of the Nuclease Domain of Adeno-Associated Virus Rep

• Published in: Molecular cell 2002-08, Vol.10 (2), p.327-337
• Main Authors: Hickman, Alison Burgess, Ronning, Donald R, Kotin, Robert M, Dyda, Fred
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Base Sequence; Binding Sites; Calorimetry; Cations, Divalent - metabolism; Crystallography, X-Ray; Dependovirus - chemistry; DNA, Viral - genetics; DNA, Viral - metabolism; DNA-Binding Proteins - chemistry; DNA-Binding Proteins - metabolism; Models, Molecular; Molecular Sequence Data; Protein Binding; Protein Folding; Protein Structure, Tertiary; Replication Origin - genetics; Sequence Homology, Amino Acid; Static Electricity; Structure-Activity Relationship; Viral Proteins - chemistry; Viral Proteins - metabolism
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/S1097-2765(02)00592-0

Adeno-associated virus (AAV), unique among animal viruses in its ability to integrate into a specific chromosomal location, is a promising vector for human gene therapy. AAV Replication (Rep) protein is essential for viral replication and integration, and its amino terminal domain possesses site-specific DNA binding and endonuclease activities required for replication initiation and integration. This domain displays a novel endonuclease fold and demonstrates an unexpected structural relationship to other viral origin binding proteins such as the papillomavirus E1 protein and the SV40 T antigen. The active site, located at the bottom of a positively charged cleft, is formed by the spatial convergence of a divalent metal ion and two conserved sequence motifs that define the rolling circle replication superfamily.