GTP‐binding Loop


The GTP‐binding loop is an evolutionarily conserved structure found in the GTPase superfamily of proteins. The GTP‐binding loop enables GTPases to bind and hydrolyse GTP molecules and makes them excellent regulators of cellular processes.

Keywords: GTPase; GTP hydrolysis; guanine nucleotide; molecular switch; Ras

Figure 1.

Primary and secondary structures of human H‐Ras protein. The amino acid sequence of the Ras protein is shown in single‐letter code. The locations of α helices and β strands are indicated above the corresponding amino acid sequences. The locations of G loops are indicated below the corresponding amino acid sequences.

Figure 2.

Ras structures in three dimensions. (a) Crystal structure of Ras complexed with the GTP analogue guanosine‐5′‐(β,γ‐imido) triphosphate (GppNp) (Pai et al., ). The main chain is represented by ribbons with the five G loops in red, the six β strands in yellow, and the remaining portion in white. The side‐chains of selected amino acid residues in the G loops are depicted with orange space‐filled models. The bound GppNp is indicated (as ball and stick form) in blue, while the Mg2+ near the γ‐phosphate is indicated in green. (b) Crystal structure of Ras complexed with GDP (Milburn et al., ). The major differences of this structure from the Ras‐GppNp complex are the bound nucleotide GDP (in light green) and the conformational changes in the switch regions as indicated. The other regions are depicted as for the Ras‐GppNp structure in (a). (Figure courtesy of Timothy Mather.)



Bar‐Sagi D and Hall A (2000) Ras and Rho GTPases: a family reunion. Cell 103: 227–238.

Barbacid M (1987) ras genes. Annual Review of Biochemistry 56: 779–827.

Bourne HR, Sanders DA and McCormick F (1990) The GTPase superfamily: a conserved switch for diverse cell functions. Nature 348: 125–132.

Chook YM and Blobel G (1999) Structure of the nuclear transport complex karyopherin‐beta2‐Ran x GppNHp. Nature 399: 230–237.

Clanton DJ, Hattori S and Shih TY (1986) Mutations of the ras gene product p21 that abolish guanine nucleotide binding. Proceedings of the National Academy of Sciences of the USA 83: 5076–5080.

Coleman DE, Berghuis AM, Lee E et al. (1994) Structures of active conformations of Gi alpha 1 and the mechanism of GTP hydrolysis. Science 265: 1405–1412.

Conklin BR and Bourne HR (1993) Structural elements of G alpha subunits that interact with G beta gamma, receptors, and effectors. Cell 73: 631–641.

Der CJ, Pan BT and Cooper GM (1986) rasH mutants deficient in GTP binding. Molecular and Cellular Biology 6: 3291–3294.

Gilman AG (1987) G proteins: transducers of receptor‐generated signals. Annual Review of Biochemistry 56: 615–649.

Goldberg J (1998) Structural basis for activation of ARF GTPase: mechanisms of guanine nucleotide exchange and GTP‐myristoyl switching. Cell 95: 237–248.

Green R and Noller HF (1997) Ribosomes and translation. Annual Review of Biochemistry 66: 679–716.

Hwang YW and Miller DL (1987) A mutation that alters the nucleotide specificity of elongation factor Tu, a GTP regulatory protein. Journal of Biological Chemistry 262(27): 13081–13085.

Kjeldgaard M, Nyborg J and Clark BF (1996) The GTP binding motif: variations on a theme. FASEB Journal 10(12): 1347–1368.

Lambright DG, Noel JP, Hamm HE and Sigler PB (1994) Structural determinants for activation of the alpha‐subunit of a heterotrimeric G protein. Nature 369: 621–628.

Li G and Liang Z (2001) Phosphate‐binding loop and Rab GTPase function: mutations at Ser29 and Ala30 of Rab5 lead to loss‐of‐function as well as gain‐of‐function phenotype. Biochemical Journal 355: 681–689.

Liang Z, Mather T and Li G (2000) GTPase mechanism and function: new insights from systematic mutational analysis of the phosphate‐binding loop residue Ala30 of Rab5. Biochemical Journal 346: 501–508.

Maegley KA, Admiraal SJ and Herschlag D (1996) Ras‐catalyzed hydrolysis of GTP: a new perspective from model studies. Proceedings of the National Academy of Sciences of the USA 93: 8160–8166.

Milburn MV, Tong L, de Vos AM et al. (1990) Molecular switch for signal transduction: structural differences between active and inactive forms of protooncogenic ras proteins. Science 247: 939–945.

Mixon MB, Lee E, Coleman DE et al. (1995) Tertiary and quaternary structural changes in Gi alpha 1 induced by GTP hydrolysis. Science 270: 954–960.

Noel JP, Hamm HE and Sigler PB (1993) The 2.2 Å crystal structure of transducin‐alpha complexed with GTP gamma S. Nature 366: 654–663.

Nuoffer C and Balch WE (1994) GTPases: multifunctional molecular switches regulating vesicular traffic. Annual Review of Biochemistry 63: 949–990.

Pai EF, Krengel U, Petsko GA et al. (1990) Refined crystal structure of the triphosphate conformation of H‐ras p21 at 1.35 Å resolution: implications for the mechanism of GTP hydrolysis. EMBO Journal 9: 2351–2359.

Prive GG, Milburn MV, Tong L et al. (1992) X‐ray crystal structures of transforming p21 ras mutants suggest a transition‐state stabilization mechanism for GTP hydrolysis. Proceedings of the National Academy of Sciences of the USA 89: 3649–3653.

Rensland H, John J, Linke R et al. (1995) Substrate and product structural requirements for binding of nucleotides to H‐ras p21: the mechanism of discrimination between guanosine and adenosine nucleotides. Biochemistry 34(2): 593–599.

Rybin V, Ullrich O, Rubino M et al. (1996) GTPase activity of Rab5 acts as a timer for endocytic membrane fusion. Nature 383: 266–269.

Schlichting I, Almo SC, Rapp G et al. (1990) Time‐resolved X‐ray crystallographic study of the conformational change in Ha‐Ras p21 protein on GTP hydrolysis. Nature 345: 309–315.

Schmidt G, Lenzen C, Simon I et al. (1996) Biochemical and biological consequences of changing the specificity of p21ras from guanosine to xanthosine nucleotides. Oncogene 12(1): 87–96.

Seeburg PH, Colby WW, Capon DJ, Goedel DV and Levinson AD (1984) Biological properties of human c‐Ha‐ras1 genes mutated at codon 12. Nature 312: 71–75.

Sigal IS, Gibbs JB, D'Alonzo JS et al. (1986) Mutant ras‐encoded proteins with altered nucleotide binding exert dominant biological effects. Proceedings of the National Academy of Sciences of the USA 83(4): 952–956.

Stroupe C and Brunger AT (2000) Crystal structures of a Rab protein in its inactive and active conformations. Journal of Molecular Biology 304(4): 585–598.

Vetter IR and Wittinghofer A (2001) The guanine nucleotide‐binding switch in three dimensions. Science 294: 1299–1304.

Vetter IR, Nowak C, Nishimoto T, Kuhlmann J and Wittinghofer A (1999) Structure of a Ran‐binding domain complexed with Ran bound to a GTP analogue: implications for nuclear transport. Nature 398: 39–46.

Further Reading

Bourne HR, Sanders DA and McCormick F (1991) The GTPase superfamily: conserved structure and molecular mechanism. Nature 349: 117–126.

Sprang SR (1997) G protein mechanisms: insights from structural analysis. Annual Review of Biochemistry 66: 639.

Wittinghofer A (2000) The functioning of molecular switches in three dimensions. In: Hall A (ed.) GTPases, pp. 244–310. New York: Oxford University Press

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Li, Guangpu(Mar 2003) GTP‐binding Loop. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1038/npg.els.0003052]