1nau

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NMR Solution Structure of the Glucagon Antagonist [desHis1, desPhe6, Glu9]Glucagon Amide in the Presence of Perdeuterated Dodecylphosphocholine Micelles

Structural highlights

1nau is a 1 chain structure with sequence from Homo sapiens. Full experimental information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:Solution NMR, 16 models
Ligands:NH2
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

GLUC_HUMAN Glucagon plays a key role in glucose metabolism and homeostasis. Regulates blood glucose by increasing gluconeogenesis and decreasing glycolysis. A counterregulatory hormone of insulin, raises plasma glucose levels in response to insulin-induced hypoglycemia. Plays an important role in initiating and maintaining hyperglycemic conditions in diabetes.[1] [2] [3] GLP-1 is a potent stimulator of glucose-dependent insulin release. Play important roles on gastric motility and the suppression of plasma glucagon levels. May be involved in the suppression of satiety and stimulation of glucose disposal in peripheral tissues, independent of the actions of insulin. Have growth-promoting activities on intestinal epithelium. May also regulate the hypothalamic pituitary axis (HPA) via effects on LH, TSH, CRH, oxytocin, and vasopressin secretion. Increases islet mass through stimulation of islet neogenesis and pancreatic beta cell proliferation. Inhibits beta cell apoptosis.[4] [5] [6] GLP-2 stimulates intestinal growth and up-regulates villus height in the small intestine, concomitant with increased crypt cell proliferation and decreased enterocyte apoptosis. The gastrointestinal tract, from the stomach to the colon is the principal target for GLP-2 action. Plays a key role in nutrient homeostasis, enhancing nutrient assimilation through enhanced gastrointestinal function, as well as increasing nutrient disposal. Stimulates intestinal glucose transport and decreases mucosal permeability.[7] [8] [9] Oxyntomodulin significantly reduces food intake. Inhibits gastric emptying in humans. Suppression of gastric emptying may lead to increased gastric distension, which may contribute to satiety by causing a sensation of fullness.[10] [11] [12] Glicentin may modulate gastric acid secretion and the gastro-pyloro-duodenal activity. May play an important role in intestinal mucosal growth in the early period of life.[13] [14] [15]

Publication Abstract from PubMed

Glucagon, a 29-residue peptide hormone, plays an important role in glucose homeostasis and in diabetes mellitus. Several glucagon antagonists and agonists have been developed, but limited structural information is available to clarify the basis of their biological activity. The solution structure of the potent glucagon antagonist, [desHis1, desPhe6, Glu9]glucagon amide, was determined by homonuclear 2D NMR spectroscopy at pH 6.0 and 37 degrees C in perdeuterated dodecylphosphocholine micelles. The overall backbone root-mean-square deviation (rmsd) for the structured portion (residues 7-29, glucagon numbering) of the micelle-bound 27-residue peptide is 1.36 A for the 15 lowest-energy structures, after restrained molecular dynamics simulation. The structure consists of four regions (segment backbone rmsd in A): an unstructured N-terminal segment between residues 2 and 5 (1.68), an irregular helix between residues 7 and 14 (0.79), a hinge region between residues 15 and 18 (0.54), and a well-defined alpha-helix between residues 19 and 29 (0.33). The two helices form an L-shaped structure with an angle of about 90 degrees between the helix axes. There is an extended hydrophobic cluster, which runs along the inner surface of the L-structure and incorporates the side chains of the hydrophobic residues of each of the amphipathic helices. The outer surface contains the hydrophilic side chains, with two salt bridges (D15-R18 and R17-D21) implied from close approach of the charged groups. This result is the first clear indication of an overall tertiary fold for a glucagon analogue in the micelle-bound state. The relationship of the two helical structural elements may have important implications for the biological activity of the glucagon antagonist.

NMR solution structure of the glucagon antagonist [desHis1, desPhe6, Glu9]glucagon amide in the presence of perdeuterated dodecylphosphocholine micelles.,Ying J, Ahn JM, Jacobsen NE, Brown MF, Hruby VJ Biochemistry. 2003 Mar 18;42(10):2825-35. PMID:12627948[16]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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Citations
3 reviews cite this structure
Membrane catalysis of peptide-receptor binding.
Langelaan et al. (2010)
2 more
6 other articles
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See Also

References

  1. ↑ Orskov C, Wettergren A, Holst JJ. Biological effects and metabolic rates of glucagonlike peptide-1 7-36 amide and glucagonlike peptide-1 7-37 in healthy subjects are indistinguishable. Diabetes. 1993 May;42(5):658-61. PMID:8482423
  2. ↑ Cohen MA, Ellis SM, Le Roux CW, Batterham RL, Park A, Patterson M, Frost GS, Ghatei MA, Bloom SR. Oxyntomodulin suppresses appetite and reduces food intake in humans. J Clin Endocrinol Metab. 2003 Oct;88(10):4696-701. PMID:14557443
  3. ↑ Tadokoro R, Shimizu T, Hosaka A, Kaneko N, Satoh Y, Yamashiro Y. Postnatal and postprandial changes in plasma concentrations of glicentin in term and preterm infants. Acta Paediatr. 2003 Oct;92(10):1175-9. PMID:14632334
  4. ↑ Orskov C, Wettergren A, Holst JJ. Biological effects and metabolic rates of glucagonlike peptide-1 7-36 amide and glucagonlike peptide-1 7-37 in healthy subjects are indistinguishable. Diabetes. 1993 May;42(5):658-61. PMID:8482423
  5. ↑ Cohen MA, Ellis SM, Le Roux CW, Batterham RL, Park A, Patterson M, Frost GS, Ghatei MA, Bloom SR. Oxyntomodulin suppresses appetite and reduces food intake in humans. J Clin Endocrinol Metab. 2003 Oct;88(10):4696-701. PMID:14557443
  6. ↑ Tadokoro R, Shimizu T, Hosaka A, Kaneko N, Satoh Y, Yamashiro Y. Postnatal and postprandial changes in plasma concentrations of glicentin in term and preterm infants. Acta Paediatr. 2003 Oct;92(10):1175-9. PMID:14632334
  7. ↑ Orskov C, Wettergren A, Holst JJ. Biological effects and metabolic rates of glucagonlike peptide-1 7-36 amide and glucagonlike peptide-1 7-37 in healthy subjects are indistinguishable. Diabetes. 1993 May;42(5):658-61. PMID:8482423
  8. ↑ Cohen MA, Ellis SM, Le Roux CW, Batterham RL, Park A, Patterson M, Frost GS, Ghatei MA, Bloom SR. Oxyntomodulin suppresses appetite and reduces food intake in humans. J Clin Endocrinol Metab. 2003 Oct;88(10):4696-701. PMID:14557443
  9. ↑ Tadokoro R, Shimizu T, Hosaka A, Kaneko N, Satoh Y, Yamashiro Y. Postnatal and postprandial changes in plasma concentrations of glicentin in term and preterm infants. Acta Paediatr. 2003 Oct;92(10):1175-9. PMID:14632334
  10. ↑ Orskov C, Wettergren A, Holst JJ. Biological effects and metabolic rates of glucagonlike peptide-1 7-36 amide and glucagonlike peptide-1 7-37 in healthy subjects are indistinguishable. Diabetes. 1993 May;42(5):658-61. PMID:8482423
  11. ↑ Cohen MA, Ellis SM, Le Roux CW, Batterham RL, Park A, Patterson M, Frost GS, Ghatei MA, Bloom SR. Oxyntomodulin suppresses appetite and reduces food intake in humans. J Clin Endocrinol Metab. 2003 Oct;88(10):4696-701. PMID:14557443
  12. ↑ Tadokoro R, Shimizu T, Hosaka A, Kaneko N, Satoh Y, Yamashiro Y. Postnatal and postprandial changes in plasma concentrations of glicentin in term and preterm infants. Acta Paediatr. 2003 Oct;92(10):1175-9. PMID:14632334
  13. ↑ Orskov C, Wettergren A, Holst JJ. Biological effects and metabolic rates of glucagonlike peptide-1 7-36 amide and glucagonlike peptide-1 7-37 in healthy subjects are indistinguishable. Diabetes. 1993 May;42(5):658-61. PMID:8482423
  14. ↑ Cohen MA, Ellis SM, Le Roux CW, Batterham RL, Park A, Patterson M, Frost GS, Ghatei MA, Bloom SR. Oxyntomodulin suppresses appetite and reduces food intake in humans. J Clin Endocrinol Metab. 2003 Oct;88(10):4696-701. PMID:14557443
  15. ↑ Tadokoro R, Shimizu T, Hosaka A, Kaneko N, Satoh Y, Yamashiro Y. Postnatal and postprandial changes in plasma concentrations of glicentin in term and preterm infants. Acta Paediatr. 2003 Oct;92(10):1175-9. PMID:14632334
  16. ↑ Ying J, Ahn JM, Jacobsen NE, Brown MF, Hruby VJ. NMR solution structure of the glucagon antagonist [desHis1, desPhe6, Glu9]glucagon amide in the presence of perdeuterated dodecylphosphocholine micelles. Biochemistry. 2003 Mar 18;42(10):2825-35. PMID:12627948 doi:10.1021/bi026629r

Contents


PDB ID 1nau

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