PDBsum entry 1xts

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Signaling protein PDB id
Protein chain
171 a.a. *
Waters ×30
* Residue conservation analysis
PDB id:
Name: Signaling protein
Title: Structure of small gtpase human rheb in complex with gtp
Structure: Gtp-binding protein rheb. Chain: a. Fragment: gtpase domain. Synonym: ras homolog enriched in brain. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: rheb. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.
2.80Å     R-factor:   0.231     R-free:   0.277
Authors: Y.Yu,J.Ding
Key ref:
Y.Yu et al. (2005). Structural basis for the unique biological function of small GTPase RHEB. J Biol Chem, 280, 17093-17100. PubMed id: 15728574 DOI: 10.1074/jbc.M501253200
24-Oct-04     Release date:   08-Mar-05    
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Protein chain
Pfam   ArchSchema ?
Q15382  (RHEB_HUMAN) -  GTP-binding protein Rheb
184 a.a.
171 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 3 residue positions (black crosses)

 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     intracellular   14 terms 
  Biological process     signal transduction   7 terms 
  Biochemical function     nucleotide binding     6 terms  


DOI no: 10.1074/jbc.M501253200 J Biol Chem 280:17093-17100 (2005)
PubMed id: 15728574  
Structural basis for the unique biological function of small GTPase RHEB.
Y.Yu, S.Li, X.Xu, Y.Li, K.Guan, E.Arnold, J.Ding.
The small GTPase Rheb displays unique biological and biochemical properties different from other small GTPases and functions as an important mediator between the tumor suppressor proteins TSC1 and TSC2 and the mammalian target of rapamycin to stimulate cell growth. We report here the three-dimensional structures of human Rheb in complexes with GDP, GTP, and GppNHp (5'-(beta,gamma-imide)triphosphate), which reveal novel structural features of Rheb and provide a molecular basis for its distinct properties. During GTP/GDP cycling, switch I of Rheb undergoes conformational change while switch II maintains a stable, unusually extended conformation, which is substantially different from the alpha-helical conformation seen in other small GTPases. The unique switch II conformation results in a displacement of Gln64 (equivalent to the catalytic Gln61 of Ras), making it incapable of participating in GTP hydrolysis and thus accounting for the low intrinsic GTPase activity of Rheb. This rearrangement also creates space to accommodate the side chain of Arg15, avoiding its steric hindrance with the catalytic residue and explaining its noninvolvement in GTP hydrolysis. Unlike Ras, the phosphate moiety of GTP in Rheb is shielded by the conserved Tyr35 of switch I, leading to the closure of the GTP-binding site, which appears to prohibit the insertion of a potential arginine finger from its GTPase-activating protein. Taking the genetic, biochemical, biological, and structural data together, we propose that Rheb forms a new group of the Ras/Rap subfamily and uses a novel GTP hydrolysis mechanism that utilizes Asn1643 of the tuberous sclerosis complex 2 GTPase-activating protein domain instead of Gln64 of Rheb as the catalytic residue.
  Selected figure(s)  
Figure 1.
FIG. 1. Representative SIGMAA-weighted 2F[o] - F[c] composite omit maps (1 contour level) at the switch II region. a, the RHEB-GDP complex. b, the RHEB-GTP complex. c, the RHEB-GppNHp complex. The final coordinates of the structures are shown as ball-and-stick models.
Figure 3.
FIG. 3. Structure of the catalytic active site region. a, comparison of RHEB in complexes with GppNHp and GDP. b, comparison of RHEB with Ras in their complexes with GppNHp. The color-coding scheme is the same as in Fig. 2. Residues in the RHEB-GppNHp complex are shown with yellow side chains and labels; residues in other complexes are shown with gray side chains without labels. c, molecular surface of the catalytic active site in the structure of the RHEB-GppNHp complex (left panel) and in the structure of the Ras-GppNHp complex (right panel).
  The above figures are reprinted by permission from the ASBMB: J Biol Chem (2005, 280, 17093-17100) copyright 2005.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21336308 M.Zheng, Y.H.Wang, X.N.Wu, S.Q.Wu, B.J.Lu, M.Q.Dong, H.Zhang, P.Sun, S.C.Lin, K.L.Guan, and J.Han (2011).
Inactivation of Rheb by PRAK-mediated phosphorylation is essential for energy-depletion-induced suppression of mTORC1.
  Nat Cell Biol, 13, 263-272.  
20018863 M.T.Mazhab-Jafari, C.B.Marshall, M.Smith, G.M.Gasmi-Seabrook, V.Stambolic, R.Rottapel, B.G.Neel, and M.Ikura (2010).
Real-time NMR study of three small GTPases reveals that fluorescent 2'(3')-O-(N-methylanthraniloyl)-tagged nucleotides alter hydrolysis and exchange kinetics.
  J Biol Chem, 285, 5132-5136.  
20685651 S.Karassek, C.Berghaus, M.Schwarten, C.G.Goemans, N.Ohse, G.Kock, K.Jockers, S.Neumann, S.Gottfried, C.Herrmann, R.Heumann, and R.Stoll (2010).
Ras homolog enriched in brain (Rheb) enhances apoptotic signaling.
  J Biol Chem, 285, 33979-33991.
PDB code: 2l0x
19451232 M.N.Lee, S.H.Ha, J.Kim, A.Koh, C.S.Lee, J.H.Kim, H.Jeon, D.H.Kim, P.G.Suh, and S.H.Ryu (2009).
Glycolytic flux signals to mTOR through glyceraldehyde-3-phosphate dehydrogenase-mediated regulation of Rheb.
  Mol Cell Biol, 29, 3991-4001.  
19620394 T.Murai, Y.Nakase, K.Fukuda, Y.Chikashige, C.Tsutsumi, Y.Hiraoka, and T.Matsumoto (2009).
Distinctive responses to nitrogen starvation in the dominant active mutants of the fission yeast Rheb GTPase.
  Genetics, 183, 517-527.  
19299511 T.Sato, A.Nakashima, L.Guo, and F.Tamanoi (2009).
Specific activation of mTORC1 by Rheb G-protein in vitro involves enhanced recruitment of its substrate protein.
  J Biol Chem, 284, 12783-12791.  
19570981 X.Dong, B.Yang, Y.Li, C.Zhong, and J.Ding (2009).
Molecular basis of the acceleration of the GDP-GTP exchange of human ras homolog enriched in brain by human translationally controlled tumor protein.
  J Biol Chem, 284, 23754-23764.
PDB code: 3ebm
18309292 A.Scrima, C.Thomas, D.Deaconescu, and A.Wittinghofer (2008).
The Rap-RapGAP complex: GTP hydrolysis without catalytic glutamine and arginine residues.
  EMBO J, 27, 1145-1153.
PDB code: 3brw
18413257 T.Sato, A.Umetsu, and F.Tamanoi (2008).
Characterization of the Rheb-mTOR signaling pathway in mammalian cells: constitutive active mutants of Rheb and mTOR.
  Methods Enzymol, 438, 307-320.  
17984325 I.I.Rybkin, M.S.Kim, S.Bezprozvannaya, X.Qi, J.A.Richardson, C.F.Plato, J.A.Hill, R.Bassel-Duby, and E.N.Olson (2007).
Regulation of atrial natriuretic peptide secretion by a novel Ras-like protein.
  J Cell Biol, 179, 527-537.  
16262791 J.Urano, M.J.Comiso, L.Guo, P.J.Aspuria, R.Deniskin, A.P.Tabancay, J.Kato-Stankiewicz, and F.Tamanoi (2005).
Identification of novel single amino acid changes that result in hyperactivation of the unique GTPase, Rheb, in fission yeast.
  Mol Microbiol, 58, 1074-1086.  
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 code is shown on the right.