High Resolution Crystal Structure of Human Rab9 GTPase

• Published in: The Journal of biological chemistry 2004-09, Vol.279 (38), p.40204-40208
• Main Authors: Chen, Liqing, DiGiammarino, Enrico, Zhou, Xiaoyin E., Wang, Yujun, Toh, Diana, Hodge, Thomas W., Meehan, Edward J.
• Format: Article
• Language: English
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M407114200

Rab GTPases and their effectors facilitate vesicular transport by tethering donor vesicles to their respective target membranes. Rab9 mediates late endosome to trans-Golgi transport and has recently been found to be a key cellular component for human immunodeficiency virus-1, Ebola, Marburg, and measles virus replication, suggesting that it may be a novel target in the development of broad spectrum antiviral drugs. As part of our structure-based drug design program, we have determined the crystal structure of a C-terminally truncated human Rab9 (residues 1-177) to 1.25-Å resolution. The overall structure shows a characteristic nucleotide binding fold consisting of a six-stranded β-sheet surrounded by five α-helices with a tightly bound GDP molecule in the active site. Structure-based sequence alignment of Rab9 with other Rab proteins reveals that its active site consists of residues highly conserved in the Rab GTPase family, implying a common catalytic mechanism. However, Rab9 contains seven regions that are significantly different in conformation from other Rab proteins. Some of those regions coincide with putative effector-binding sites and switch I and switch II regions identified by structure/sequence alignments. The Rab9 structure at near atomic resolution provides an excellent model for structure-based antiviral drug design.