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Chemical Compound Review

GMP-Pnp     [[[[(2R,3S,4R,5R)-5-(2-amino- 6-oxo-3H...

Synonyms: GppNHp, GppNP, GDP-NP, CHEMBL1233085, CHEBI:42862, ...
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Disease relevance of GMP-Pnp

  • Pertussis toxin (PTX) and 5-guanylylimidodiphosphate (GppNHp) mimicked the outcome of ICI174864 pretreatment in promoting the loss of agonist binding sites [1].
  • The three-dimensional modeling of SsG-EcMC indicated only small structural differences compared to the Thermus aquaticus EF-Tu in the ternary complex with aa-tRNA and GppNHp, which did not account for the observed inability to interact with aa-tRNA [2].
  • Microsphere embolism (ME) decreased the activity of Ca(2+)/calmodulin (CaM)-sensitive AC in the ipsilateral hemisphere throughout the experiment, whereas the basal and 5'-guanylyl imidodiphosphate (Gpp(NH)p)-sensitive AC activities were not altered [3].
  • Addition of a G(i/o)-protein mix to E. coli membranes increased high affinity [(3)H]7-OH-DPAT binding in a concentration-dependent manner at hD(2) and hD(3) receptors; this effect was reversed by addition of GppNHp [4].
  • 6 The affinity constants of agonists for the H and L forms of the receptors were not changed by GppNHp [5].

High impact information on GMP-Pnp

  • Here, we report the three-dimensional structure of a complex between Ran bound to the nonhydrolyzable GTP analog GppNHp and a 462-residue fragment from Importin beta [6].
  • Ran x GppNHp in the complex shows extensive structural rearrangement, compared to Ran GDP, in regions contacting karyopherin-beta2 [7].
  • Structure of the nuclear transport complex karyopherin-beta2-Ran x GppNHp [7].
  • The X-ray crystal structure of the complex between the Ras-related protein Rap1A in the GTP-analogue (GppNHp) form and the Ras-binding domain (RBD) of the Ras effector molecule c-Raf1, a Ser/Thr-specific protein kinase, has been solved to a resolution of 2.2 A [8].
  • Here we report the crystal structure of the complex between the Ral-binding domain of Sec5 and RalA bound to a non-hydrolyzable GTP analog (GppNHp) at 2.1 A resolution, providing the first structural insights into the mechanism and specificity of sec6/8 regulation [9].

Chemical compound and disease context of GMP-Pnp

  • The binding of the agonist carbamylcholine to muscarinic receptors in rat heart myocytes from young and aged cultures and in rat atrial membranes has been measured in the absence and presence of GppNHp, pertussis toxin, and/or batrachotoxin [10].
  • Forskolin (1 microM) increased adenylate cyclase activity at least ten-fold and the inhibitory effect of GppNHp was reduced but not abolished by pertussis toxin [11].
  • In contrast, adenylyl cyclase activity stimulated by 1 mumol/L (-)-isoproterenol in the presence of 10 mumol/L GppNHp was not significantly reduced (n = 10), a finding that indicates relative preservation of beta-adrenoceptor-mediated adenylyl cyclase activity in ischemia [12].
  • We observe that pertussis toxin increases TER, while AIF3 and carbamil choline (carbachol) inhibit it, and 5-guanylylimidodiphosphate (GTPTs) blocks the development of a cell border pattern of ZO-1, suggesting that G-proteins are involved [13].
  • In the presence of the beta-adrenergic agonist, isoproterenol, GDP beta S fails to support stimulation of C6 glioma membrane adenylate cyclase and inhibits GppNHp- or GTP gamma S-mediated stimulation of that enzyme.(ABSTRACT TRUNCATED AT 250 WORDS)[14]

Biological context of GMP-Pnp

  • When GppNHp was used the rate of activation of the cyclase in a strain harboring a multicopy plasmid of CDC25 was 7.0-fold higher than the rate in an isogenic strain with the cdc25-2 mutation [15].
  • Although GDP and 5'-guanylyl imidodiphosphate also influence the phosphorylation of these proteins, we present evidence that the effects of p21 ras protein are not simply due to their bound GDP [16].
  • MANT-GTP gamma S/MANT-GppNHp had lower affinities for G alpha(s) and G alpha(i) than GTP gamma S/GppNHp as assessed by inhibition of GTP hydrolysis of receptor-G alpha fusion proteins [17].
  • 5'-Guanylylimidodiphosphate (GppNHp) selectively and potently (IC50 = 0.1 microM) inhibited high affinity binding of the tritiated agonist, and this inhibition resulted from the GppNHp-induced conversion of the high into the lower affinity sites for [3H]etorphine [18].
  • Scatchard analysis revealed that GppNHp induced a 3.8-fold increase in the dissociation constant without a significant change in the number of binding sites, suggesting that the GppNHp-induced decrease in 17 alpha,20 beta-DP binding is due to the decrease in binding affinity between 17 alpha,20 beta-DP and its receptors [19].

Anatomical context of GMP-Pnp


Associations of GMP-Pnp with other chemical compounds

  • However, in F1B hamsters, training decreased ACAs stimulated by GppNHp, sodium fluoride, and forskolin, with a reduced functional activity of Gs [25].
  • The influence of the guanosine 5'-triphosphate (GTP) analogue GppNHp on binding indicated that the granulocyte receptor was linked to a G protein [26].
  • Analysis of the curves showed that the EGTA membranes had an increased number of high affinity agonist sites (Kd, 42 nM) and that guanyl-5'-yl imidodiphosphate (GppNHp) converted these to low affinity sites (Kd, 1039 nM) [23].
  • Moreover, reducing the free calcium concentration to less than 10(-9) M by adding 10 mM EGTA to the permeabilization medium dissociated the effects of GppNHp and DG on secretion, increasing GppNHp-stimulated PTH release while reducing PTH secretion evoked by DG.(ABSTRACT TRUNCATED AT 250 WORDS)[27]
  • Addition of dioctanoylglycerol, however, a synthetic diacylglycerol (DG) that activates protein kinase C, produced a much smaller increment in PTH release than GppNHp [27].

Gene context of GMP-Pnp

  • 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 [28].
  • Crude extract and plasma membrane fraction of cyr1 mutant cells had no adenylate cyclase activity when assayed with GTP or 5'-guanylyl imidodiphosphate in the presence of Mn2+ or Mg2+ [29].
  • The presence of 5'-guanylylimidodiphosphate (GppNHp) or NaCl reduced the agonist labeling of hGALR in ENT membranes [30].
  • We present the 1.5 A high-resolution crystal structure of Ypt51 in its active, GppNHp-bound conformation [31].
  • Incubation of both types of membranes with GTP or its analogue, GppNHp, resulted in a dose-dependent inhibition of specific binding suggesting that the myometrial CRH receptor is linked to a G regulatory protein.(ABSTRACT TRUNCATED AT 250 WORDS)[32]

Analytical, diagnostic and therapeutic context of GMP-Pnp

  • Prolonged ultracentrifugation of the complex also causes partial dissociation of the beta gamma subunits from alpha s (GppNHp) [33].
  • Internal perfusion of GppNHp resulted in a near-complete (approximately 80%) and irreversible inhibition of Iso-stimulated ICa [34].
  • Intracellular dialysis with any of three different activators of G proteins (GTP gamma S, GppNHp, or AlF-4) completely inhibited the inward rectifier K+ conductance with a half-time for decline averaging approximately 300 s after "break-in" to achieve whole-cell recording [35].
  • The concentration of [3H]N-methylscopolamine binding sites and muscarinic M1 and M2 receptor subtypes, as well as the affinity of muscarinic receptors and their sensitivity to modulation by 5-guanylylimidodiphosphate were analysed by quantitative receptor autoradiography [36].
  • Rab7: crystallization of intact and C-terminal truncated constructs complexed with GDP and GppNHp [37].


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  2. A chimeric elongation factor containing the putative guanine nucleotide binding domain of archaeal EF-1 alpha and the M and C domains of eubacterial EF-Tu. Arcari, P., Masullo, M., Arcucci, A., Ianniciello, G., de Paola, B., Bocchini, V. Biochemistry (1999) [Pubmed]
  3. Impairment of adenylyl cyclase and of spatial memory function after microsphere embolism in rats. Nagakura, A., Miyake-Takagi, K., Takagi, N., Fukui, M., Takeo, S. J. Neurosci. Res. (2002) [Pubmed]
  4. G-protein sensitivity of ligand binding to human dopamine D(2) and D(3) receptors expressed in Escherichia coli: clues for a constrained D(3) receptor structure. Vanhauwe, J.F., Josson, K., Luyten, W.H., Driessen, A.J., Leysen, J.E. J. Pharmacol. Exp. Ther. (2000) [Pubmed]
  5. The effects of agonists on the components of the cardiac muscarinic receptor. Burgen, A.S. Br. J. Pharmacol. (1987) [Pubmed]
  6. Structural view of the Ran-Importin beta interaction at 2.3 A resolution. Vetter, I.R., Arndt, A., Kutay, U., Görlich, D., Wittinghofer, A. Cell (1999) [Pubmed]
  7. Structure of the nuclear transport complex karyopherin-beta2-Ran x GppNHp. Chook, Y.M., Blobel, G. Nature (1999) [Pubmed]
  8. The 2.2 A crystal structure of the Ras-binding domain of the serine/threonine kinase c-Raf1 in complex with Rap1A and a GTP analogue. Nassar, N., Horn, G., Herrmann, C., Scherer, A., McCormick, F., Wittinghofer, A. Nature (1995) [Pubmed]
  9. Structural basis of the interaction between RalA and Sec5, a subunit of the sec6/8 complex. Fukai, S., Matern, H.T., Jagath, J.R., Scheller, R.H., Brunger, A.T. EMBO J. (2003) [Pubmed]
  10. A model for the interaction of muscarinic receptors, agonists, and two distinct effector substances. Minton, A.P., Sokolovsky, M. Biochemistry (1990) [Pubmed]
  11. Pertussis toxin reverses Gpp(NH)p inhibition of basal and forskolin activated adipocyte adenylate cyclase. Fain, J.N., O'Donnell, C.J., Mills, I., Gárciá-Sáinz, J.A. Biochem. Biophys. Res. Commun. (1983) [Pubmed]
  12. Preserved beta-adrenoceptor-mediated adenylyl cyclase activity despite receptor and postreceptor dysfunction in acute myocardial ischemia. Wolff, A.A., Hines, D.K., Karliner, J.S. Am. Heart J. (1994) [Pubmed]
  13. Assembly and sealing of tight junctions: possible participation of G-proteins, phospholipase C, protein kinase C and calmodulin. Balda, M.S., González-Mariscal, L., Contreras, R.G., Macias-Silva, M., Torres-Marquez, M.E., García-Sáinz, J.A., Cereijido, M. J. Membr. Biol. (1991) [Pubmed]
  14. Guanosine-5'-O-thiodiphosphate functions as a partial agonist for the receptor-independent stimulation of neural adenylate cyclase. Rasenick, M.M., Hughes, J.M., Wang, N. Brain Res. (1989) [Pubmed]
  15. In vitro reconstitution of cdc25 regulated S. cerevisiae adenylyl cyclase and its kinetic properties. Engelberg, D., Simchen, G., Levitzki, A. EMBO J. (1990) [Pubmed]
  16. p21 ras proteins and guanine nucleotides modulate the phosphorylation of 36- and 17-kilodalton mitochondria-associated proteins. Backer, J.M., Weinstein, I.B. Proc. Natl. Acad. Sci. U.S.A. (1986) [Pubmed]
  17. 2'(3')-O-(N-methylanthraniloyl)-substituted GTP analogs: a novel class of potent competitive adenylyl cyclase inhibitors. Gille, A., Seifert, R. J. Biol. Chem. (2003) [Pubmed]
  18. 5'-Guanylylimidodiphosphate decreases affinity for agonists and apparent molecular size of a frog brain opioid receptor in digitonin solution. Mollereau, C., Pascaud, A., Baillat, G., Mazarguil, H., Puget, A., Meunier, J.C. J. Biol. Chem. (1988) [Pubmed]
  19. Involvement of an inhibitory G-protein in the signal transduction pathway of maturation-inducing hormone (17 alpha,20 beta-dihydroxy-4-pregnen-3-one) action in rainbow trout (Oncorhynchus mykiss) oocytes. Yoshikuni, M., Nagahama, Y. Dev. Biol. (1994) [Pubmed]
  20. Salts promote activation of fat cell adenylate cyclase by GTP: special role for sodium ion. Katz, M.S., Partilla, J.S., Piñeyro, M.A., Schneyer, C.R., Gregerman, R.I. Proc. Natl. Acad. Sci. U.S.A. (1981) [Pubmed]
  21. Polylysine-containing peptides, including the carboxyl-terminal segment of the human c-Ki-ras 2 protein, affect the activity of some key membrane enzymes. Gatica, M., Allende, C.C., Antonelli, M., Allende, J.E. Proc. Natl. Acad. Sci. U.S.A. (1987) [Pubmed]
  22. Cytosolic activator of adenylate cyclase: Reconstitution, characterization, and mechanism of action. Sahyoun, N., LeVine, H., Stenbuck, P., Cuatrecasas, P. Proc. Natl. Acad. Sci. U.S.A. (1983) [Pubmed]
  23. Studies on the hepatic alpha 1-adrenergic receptor. Modulation of guanine nucleotide effects by calcium, temperature, and age. Lynch, C.J., Charest, R., Blackmore, P.F., Exton, J.H. J. Biol. Chem. (1985) [Pubmed]
  24. Assembly and disassembly properties of microtubules formed in the presence of GTP, 5'-guanylyl imidodiphosphate, and 5'-guanylyl methylenediphosphate. Terry, B.J., Purich, D.L. J. Biol. Chem. (1980) [Pubmed]
  25. Chronic dynamic exercise improves a functional abnormality of the G stimulatory protein in cardiomyopathic BIO 53.58 Syrian hamsters. Tomita, T., Murakami, T., Iwase, T., Nagai, K., Fujita, J., Sasayama, S. Circulation (1994) [Pubmed]
  26. Human granulocytes contain an opiate alkaloid-selective receptor mediating inhibition of cytokine-induced activation and chemotaxis. Makman, M.H., Bilfinger, T.V., Stefano, G.B. J. Immunol. (1995) [Pubmed]
  27. Mechanisms underlying the stimulation of PTH release by GppNHp in permeabilized bovine parathyroid cells. Leboff, M.S., Oetting, M., Brown, E.M. J. Bone Miner. Res. (1990) [Pubmed]
  28. Structural basis for the unique biological function of small GTPase RHEB. Yu, Y., Li, S., Xu, X., Li, Y., Guan, K., Arnold, E., Ding, J. J. Biol. Chem. (2005) [Pubmed]
  29. Identification of the structural gene and nonsense alleles for adenylate cyclase in Saccharomyces cerevisiae. Matsumoto, K., Uno, I., Ishikawa, T. J. Bacteriol. (1984) [Pubmed]
  30. Characterization and localization of galanin receptors in human entorhinal cortex. Deecher, D.C., Mash, D.C., Staley, J.K., Mufson, E.J. Regul. Pept. (1998) [Pubmed]
  31. High-resolution crystal structure of S. cerevisiae Ypt51(DeltaC15)-GppNHp, a small GTP-binding protein involved in regulation of endocytosis. Esters, H., Alexandrov, K., Constantinescu, A.T., Goody, R.S., Scheidig, A.J. J. Mol. Biol. (2000) [Pubmed]
  32. The human myometrial CRH receptor: G proteins and second messengers. Grammatopoulos, D., Milton, N.G., Hillhouse, E.W. Mol. Cell. Endocrinol. (1994) [Pubmed]
  33. Beta subunit copurifies with GppNHp-activated adenylyl cyclase. Marbach, I., Bar-Sinai, A., Minich, M., Levitzki, A. J. Biol. Chem. (1990) [Pubmed]
  34. Regulation of Ca2+ current in frog ventricular cardiomyocytes by guanosine 5'-triphosphate analogues and isoproterenol. Parsons, T.D., Hartzell, H.C. J. Gen. Physiol. (1993) [Pubmed]
  35. G protein control of potassium channel activity in a mast cell line. McCloskey, M.A., Cahalan, M.D. J. Gen. Physiol. (1990) [Pubmed]
  36. Muscarinic desensitization after septal lesions in rat hippocampus: evidence for the involvement of G-proteins. Bauer, A., Schulz, J.B., Zilles, K. Neuroscience (1992) [Pubmed]
  37. Rab7: crystallization of intact and C-terminal truncated constructs complexed with GDP and GppNHp. Brachvogel, V., Neu, M., Metcalf, P. Proteins (1997) [Pubmed]
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