 |
PDBsum entry 1wms
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Protein transport
|
PDB id
|
|
|
|
1wms
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
Contents |
 |
|
|
|
|
|
|
|
|
|
|
|
|
* Residue conservation analysis
|
|
|
|
|
References listed in PDB file
|
|
|
Key reference
|
|
|
Title
|
|
High resolution crystal structure of human rab9 gtpase: a novel antiviral drug target.
|
|
|
Authors
|
|
L.Chen,
E.Digiammarino,
X.E.Zhou,
Y.Wang,
D.Toh,
T.W.Hodge,
E.J.Meehan.
|
|
|
Ref.
|
|
J Biol Chem, 2004,
279,
40204-40208.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
Abstract
|
|
|
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.
|
|
|
|
|
|
|
|
Figure 2.
FIG. 2. Stereoview of the C  race of Rab9. Every
10th residue and both N and C termini are labeled. Residues 1,
35-38, and 176-177 are missing from the refined model and are
not shown.
|
|
Figure 5.
FIG. 5. Structure-based sequence alignment of Rab9 with the
most similar structures. The sequence number for the first
residue of each line is indicated on the left. The positions of
the secondary structural elements in Rab9 are indicated by
underlining the sequence and labeling as in Fig. 1. Residues
that are highly conserved in the Rab GTPase family are indicated
in boldface type. Residues that are known to contact GDP in
protein-GDP complex structures are indicated in red. Additional
residues that would interact with the  -phosphate in
protein-GTP analog complex structures are shown in purple. The
seven regions that show high degree of conformational variation
among the superimposed structures (see Fig. 6) are highlighted
in gold and labeled. See Table III for protein abbreviations and
references.
|
|
|
|
|
|
The above figures are
reprinted
by permission from the ASBMB:
J Biol Chem
(2004,
279,
40204-40208)
copyright 2004.
|
|
|
|
|
|
|
