High resolution crystal structure of human Rab9 GTPase: a novel antiviral drug target.
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-A resolution. The overall structure shows a characteristic nucleotide binding fold consisting of a six-stranded beta-sheet surrounded by five alpha-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.
Chen
Liqing
L
Laboratory for Structural Biology, Department of Chemistry, Graduate Programs of Biotechnology, Chemistry and Materials Science, University of Alabama in Huntsville, Huntsville, Alabama 35899, USA.
DiGiammarino
Enrico
E
Zhou
Xiaoyin E
XE
Wang
Yujun
Y
Toh
Diana
D
Hodge
Thomas W
TW
Meehan
Edward J
EJ
D000595:Amino Acid Sequence; D001665:Binding Sites; D003461:Crystallography; D006153:Guanosine Diphosphate / Q000378:metabolism; D006801:Humans; D006860:Hydrogen Bonding; D008969:Molecular Sequence Data; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D020691:rab GTP-Binding Proteins / Q000737:chemistry* / Q000378:metabolism
D006153:Guanosine Diphosphate; C079856:RAB9A protein, human; D020691:rab GTP-Binding Proteins