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206 a.a.
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146 a.a.
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344 a.a.
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* Residue conservation analysis
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PDB id:
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Signaling protein/signaling activator
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Title:
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Crystal structure of ran-gppnhp-ranbp1-rangap complex
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Structure:
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Gtp-binding nuclear protein ran. Chain: a, d, g, j. Synonym: ran, tc4, ran gtpase, androgen receptor-associated protein 24. Engineered: yes. Ran-specific gtpase-activating protein. Chain: b, e, h, k. Synonym: ranbp1, ran binding protein 1. Engineered: yes.
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli bl21. Expression_system_taxid: 511693. Schizosaccharomyces pombe. Fission yeast. Organism_taxid: 4896. Expressed in: escherichia coli.
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Biol. unit:
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Trimer (from
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Resolution:
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2.70Å
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R-factor:
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0.237
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R-free:
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0.267
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Authors:
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M.J.Seewald,C.Koerner,A.Wittinghofer,I.R.Vetter
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Key ref:
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M.J.Seewald
et al.
(2002).
RanGAP mediates GTP hydrolysis without an arginine finger.
Nature,
415,
662-666.
PubMed id:
DOI:
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Date:
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10-Oct-01
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Release date:
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13-Feb-02
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PROCHECK
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Headers
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References
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P62826
(RAN_HUMAN) -
GTP-binding nuclear protein Ran from Homo sapiens
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Seq:
Struc:
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216 a.a.
206 a.a.
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DOI no:
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Nature
415:662-666
(2002)
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PubMed id:
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RanGAP mediates GTP hydrolysis without an arginine finger.
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M.J.Seewald,
C.Körner,
A.Wittinghofer,
I.R.Vetter.
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ABSTRACT
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GTPase-activating proteins (GAPs) increase the rate of GTP hydrolysis on guanine
nucleotide-binding proteins by many orders of magnitude. Studies with Ras and
Rho have elucidated the mechanism of GAP action by showing that their catalytic
machinery is both stabilized by GAP binding and complemented by the insertion of
a so-called 'arginine finger' into the phosphate-binding pocket. This has been
proposed as a universal mechanism for GAP-mediated GTP hydrolysis. Ran is a
nuclear Ras-related protein that regulates both transport between the nucleus
and cytoplasm during interphase, and formation of the mitotic spindle and/or
nuclear envelope in dividing cells. Ran-GTP is hydrolysed by the combined action
of Ran-binding proteins (RanBPs) and RanGAP. Here we present the
three-dimensional structure of a Ran-RanBP1-RanGAP ternary complex in the ground
state and in a transition-state mimic. The structure and biochemical experiments
show that RanGAP does not act through an arginine finger, that the basic
machinery for fast GTP hydrolysis is provided exclusively by Ran and that
correct positioning of the catalytic glutamine is essential for catalysis.
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Selected figure(s)
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Figure 2.
Figure 2: Details of the Ran–RanGAP interface. a, Worm plot
of Ran and RanGAP, with colours as in Fig. 1 and important
residues shown in ball and stick representation. The uncomplexed
RanGAP (cyan) is superimposed; arrows indicate the movement of
Lys 76 and Arg 74, and asterisk symbolizes the potential clash
of Leu 43 and Lys 76 on complex formation. b, Switch II of Ran
(green) superimposed on the Ran–ranBD1 structure (blue),
illustrating the reorientation of Gln 69 into a catalytically
competent conformation by the residues Tyr 39 from Ran and Asn
131 fron RanGAP.
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Figure 3.
Figure 3: The active site. a, The nucleotide and relevant
residues of Ran and RanGAP; interactions are indicated by dashed
lines. The catalytic water ('W') has very weak density (probably
owing to the limited resolution) and was not included in the
final model, but is shown here to illustrate its potential
interaction partners. It sits in a similar position as in the
Ras–RasGAP complex. Asterisk denotes the hydroxyl group of Thr
42 of Ran. The rest of the side chain is omitted for clarity. b,
The 2F[o] - F[c] electron density map contoured at 1.6  for
the structure with GDP and aluminium fluoride, the latter
modelled as AlF[3].
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The above figures are
reprinted
by permission from Macmillan Publishers Ltd:
Nature
(2002,
415,
662-666)
copyright 2002.
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Figures were
selected
by an automated process.
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Literature references that cite this PDB file's key reference
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PubMed id
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Reference
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K.Langer,
C.Dian,
V.Rybin,
C.W.Müller,
and
C.Petosa
(2011).
Insights into the Function of the CRM1 Cofactor RanBP3 from the Structure of Its Ran-Binding Domain.
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PLoS One,
6,
e17011.
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PDB codes:
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N.Pawlowski,
A.Khaminets,
J.P.Hunn,
N.Papic,
A.Schmidt,
R.C.Uthaiah,
R.Lange,
G.Vopper,
S.Martens,
E.Wolf,
and
J.C.Howard
(2011).
The activation mechanism of Irga6, an interferon-inducible GTPase contributing to mouse resistance against Toxoplasma gondii.
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BMC Biol,
9,
7.
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P.L.Kastritis,
I.H.Moal,
H.Hwang,
Z.Weng,
P.A.Bates,
A.M.Bonvin,
and
J.Janin
(2011).
A structure-based benchmark for protein-protein binding affinity.
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Protein Sci,
20,
482-491.
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B.Anand,
P.Surana,
and
B.Prakash
(2010).
Deciphering the catalytic machinery in 30S ribosome assembly GTPase YqeH.
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PLoS One,
5,
e9944.
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G.Bompard,
G.Rabeharivelo,
M.Frank,
J.Cau,
C.Delsert,
and
N.Morin
(2010).
Subgroup II PAK-mediated phosphorylation regulates Ran activity during mitosis.
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J Cell Biol,
190,
807-822.
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R.D.Makde,
J.R.England,
H.P.Yennawar,
and
S.Tan
(2010).
Structure of RCC1 chromatin factor bound to the nucleosome core particle.
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Nature,
467,
562-566.
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PDB code:
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J.S.Chappie,
S.Acharya,
Y.W.Liu,
M.Leonard,
T.J.Pucadyil,
and
S.L.Schmid
(2009).
An intramolecular signaling element that modulates dynamin function in vitro and in vivo.
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Mol Biol Cell,
20,
3561-3571.
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A.Scrima,
C.Thomas,
D.Deaconescu,
and
A.Wittinghofer
(2008).
The Rap-RapGAP complex: GTP hydrolysis without catalytic glutamine and arginine residues.
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EMBO J,
27,
1145-1153.
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PDB code:
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D.Owen,
L.J.Campbell,
K.Littlefield,
K.A.Evetts,
Z.Li,
D.B.Sacks,
P.N.Lowe,
and
H.R.Mott
(2008).
The IQGAP1-Rac1 and IQGAP1-Cdc42 interactions: interfaces differ between the complexes.
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J Biol Chem,
283,
1692-1704.
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J.Sudhamsu,
G.I.Lee,
D.F.Klessig,
and
B.R.Crane
(2008).
The Structure of YqeH: AN AtNOS1/AtNOA1 ORTHOLOG THAT COUPLES GTP HYDROLYSIS TO MOLECULAR RECOGNITION.
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J Biol Chem,
283,
32968-32976.
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PDB code:
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P.R.Clarke,
and
C.Zhang
(2008).
Spatial and temporal coordination of mitosis by Ran GTPase.
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Nat Rev Mol Cell Biol,
9,
464-477.
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A.Cook,
F.Bono,
M.Jinek,
and
E.Conti
(2007).
Structural biology of nucleocytoplasmic transport.
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Annu Rev Biochem,
76,
647-671.
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E.Kanamori,
Y.Murakami,
Y.Tsuchiya,
D.M.Standley,
H.Nakamura,
and
K.Kinoshita
(2007).
Docking of protein molecular surfaces with evolutionary trace analysis.
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Proteins,
69,
832-838.
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J.L.Bos,
H.Rehmann,
and
A.Wittinghofer
(2007).
GEFs and GAPs: critical elements in the control of small G proteins.
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Cell,
129,
865-877.
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M.Stewart
(2007).
Molecular mechanism of the nuclear protein import cycle.
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Nat Rev Mol Cell Biol,
8,
195-208.
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N.Matsushima,
T.Tanaka,
P.Enkhbayar,
T.Mikami,
M.Taga,
K.Yamada,
and
Y.Kuroki
(2007).
Comparative sequence analysis of leucine-rich repeats (LRRs) within vertebrate toll-like receptors.
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BMC Genomics,
8,
124.
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T.Huyton,
J.Rossjohn,
and
M.Wilce
(2007).
Toll-like receptors: structural pieces of a curve-shaped puzzle.
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Immunol Cell Biol,
85,
406-410.
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A.S.Madrid,
and
K.Weis
(2006).
Nuclear transport is becoming crystal clear.
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Chromosoma,
115,
98.
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A.Scrima,
and
A.Wittinghofer
(2006).
Dimerisation-dependent GTPase reaction of MnmE: how potassium acts as GTPase-activating element.
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EMBO J,
25,
2940-2951.
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PDB codes:
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A.Wittinghofer
(2006).
Phosphoryl transfer in Ras proteins, conclusive or elusive?
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Trends Biochem Sci,
31,
20-23.
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L.Federici,
A.Di Matteo,
J.Fernandez-Recio,
D.Tsernoglou,
and
F.Cervone
(2006).
Polygalacturonase inhibiting proteins: players in plant innate immunity?
|
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Trends Plant Sci,
11,
65-70.
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R.C.Hillig,
and
L.Renault
(2006).
Detecting and overcoming hemihedral twinning during the MIR structure determination of Rna1p.
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Acta Crystallogr D Biol Crystallogr,
62,
750-765.
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PDB code:
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B.Hao,
N.Zheng,
B.A.Schulman,
G.Wu,
J.J.Miller,
M.Pagano,
and
N.P.Pavletich
(2005).
Structural basis of the Cks1-dependent recognition of p27(Kip1) by the SCF(Skp2) ubiquitin ligase.
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Mol Cell,
20,
9.
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PDB codes:
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E.Takeda,
M.Hieda,
J.Katahira,
and
Y.Yoneda
(2005).
Phosphorylation of RanGAP1 stabilizes its interaction with Ran and RanBP1.
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Cell Struct Funct,
30,
69-80.
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J.Choe,
M.S.Kelker,
and
I.A.Wilson
(2005).
Crystal structure of human toll-like receptor 3 (TLR3) ectodomain.
|
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Science,
309,
581-585.
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PDB code:
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M.Martínez-Vicente,
L.Yim,
M.Villarroya,
M.Mellado,
E.Pérez-Payá,
G.R.Björk,
and
M.E.Armengod
(2005).
Effects of mutagenesis in the switch I region and conserved arginines of Escherichia coli MnmE protein, a GTPase involved in tRNA modification.
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J Biol Chem,
280,
30660-30670.
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R.Mishra,
S.K.Gara,
S.Mishra,
and
B.Prakash
(2005).
Analysis of GTPases carrying hydrophobic amino acid substitutions in lieu of the catalytic glutamine: implications for GTP hydrolysis.
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Proteins,
59,
332-338.
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Y.Zhang,
and
J.Skolnick
(2005).
The protein structure prediction problem could be solved using the current PDB library.
|
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Proc Natl Acad Sci U S A,
102,
1029-1034.
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A.Kusano,
T.Yoshioka,
H.Nishijima,
H.Nishitani,
and
T.Nishimoto
(2004).
Schizosaccharomyces pombe RanGAP homolog, SpRna1, is required for centromeric silencing and chromosome segregation.
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Mol Biol Cell,
15,
4960-4970.
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A.Shurki,
and
A.Warshel
(2004).
Why does the Ras switch "break" by oncogenic mutations?
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Proteins,
55,
1.
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E.J.Helmreich
(2004).
Structural flexibility of small GTPases. Can it explain their functional versatility?
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Biol Chem,
385,
1121-1136.
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M.H.Modarressi,
M.Cheng,
H.A.Tarnasky,
N.Lamarche-Vane,
D.G.de Rooij,
Y.Ruan,
and
F.A.van der Hoorn
(2004).
A novel testicular RhoGAP-domain protein induces apoptosis.
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Biol Reprod,
71,
1980-1990.
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M.Yamada,
I.W.Mattaj,
and
Y.Yoneda
(2004).
An ATP-dependent activity that releases RanGDP from NTF2.
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J Biol Chem,
279,
36228-36234.
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O.Daumke,
M.Weyand,
P.P.Chakrabarti,
I.R.Vetter,
and
A.Wittinghofer
(2004).
The GTPase-activating protein Rap1GAP uses a catalytic asparagine.
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Nature,
429,
197-201.
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PDB code:
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P.Enkhbayar,
M.Kamiya,
M.Osaki,
T.Matsumoto,
and
N.Matsushima
(2004).
Structural principles of leucine-rich repeat (LRR) proteins.
|
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Proteins,
54,
394-403.
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P.F.Egea,
S.O.Shan,
J.Napetschnig,
D.F.Savage,
P.Walter,
and
R.M.Stroud
(2004).
Substrate twinning activates the signal recognition particle and its receptor.
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Nature,
427,
215-221.
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PDB code:
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P.P.Chakrabarti,
Y.Suveyzdis,
A.Wittinghofer,
and
K.Gerwert
(2004).
Fourier transform infrared spectroscopy on the Rap.RapGAP reaction, GTPase activation without an arginine finger.
|
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J Biol Chem,
279,
46226-46233.
|
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Z.M.Radisavljevic,
and
B.González-Flecha
(2004).
TOR kinase and Ran are downstream from PI3K/Akt in H2O2-induced mitosis.
|
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J Cell Biochem,
91,
1293-1300.
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J.K.Bell,
G.E.Mullen,
C.A.Leifer,
A.Mazzoni,
D.R.Davies,
and
D.M.Segal
(2003).
Leucine-rich repeats and pathogen recognition in Toll-like receptors.
|
| |
Trends Immunol,
24,
528-533.
|
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|
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M.J.Seewald,
A.Kraemer,
M.Farkasovsky,
C.Körner,
A.Wittinghofer,
and
I.R.Vetter
(2003).
Biochemical characterization of the Ran-RanBP1-RanGAP system: are RanBP proteins and the acidic tail of RanGAP required for the Ran-RanGAP GTPase reaction?
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Mol Cell Biol,
23,
8124-8136.
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D.L.Ippolito,
P.A.Temkin,
S.L.Rogalski,
and
C.Chavkin
(2002).
N-terminal tyrosine residues within the potassium channel Kir3 modulate GTPase activity of Galphai.
|
| |
J Biol Chem,
277,
32692-32696.
|
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H.Yaguchi,
N.Ohkura,
T.Tsukada,
and
K.Yamaguchi
(2002).
Menin, the multiple endocrine neoplasia type 1 gene product, exhibits GTP-hydrolyzing activity in the presence of the tumor metastasis suppressor nm23.
|
| |
J Biol Chem,
277,
38197-38204.
|
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J.M.Swart-Mataraza,
Z.Li,
and
D.B.Sacks
(2002).
IQGAP1 is a component of Cdc42 signaling to the cytoskeleton.
|
| |
J Biol Chem,
277,
24753-24763.
|
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M.Geymonat,
A.Spanos,
S.J.Smith,
E.Wheatley,
K.Rittinger,
L.H.Johnston,
and
S.G.Sedgwick
(2002).
Control of mitotic exit in budding yeast. In vitro regulation of Tem1 GTPase by Bub2 and Bfa1.
|
| |
J Biol Chem,
277,
28439-28445.
|
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S.Sever
(2002).
Dynamin and endocytosis.
|
| |
Curr Opin Cell Biol,
14,
463-467.
|
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|
The most recent references are shown first.
Citation data come partly from CiteXplore and partly
from an automated harvesting procedure. Note that this is likely to be
only a partial list as not all journals are covered by
either method. However, we are continually building up the citation data
so more and more references will be included with time.
Where a reference describes a PDB structure, the PDB
codes are
shown on the right.
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Links
