Glycine 119 of Bovine Growth Hormone is Critical for Growth-Promoting Activity

Chen, Wen Y.; Wight, David C.; Mehta, Bhavin V.; Wagner, Thomas E.; Kopchick, John J.

doi:10.1210/mend-5-12-1845

Cited by 163 publications

(132 citation statements)

References 45 publications

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“…This novel class of molecules consists of modified GH-core proteins, which harbor one steric mutation within binding site 2, namely the replacement of the helix ␣3 Gly with long and charged residues such as Lys or Arg. Initially introduced in the bovine hormone (G119R-bGH) (15), the Gly substitution in the human hormone was also shown to generate an antagonist (G120K/RhGH), and the crystal structure of the hGH⅐hGHR 2 complex revealed that the Arg/Lys could actually impede the formation of a functional receptor dimer (14). Subsequently, these studies have resulted in the approval of a GHR antagonist, Somavert (Pegvisomant for injection), as a drug for the treatment of acromegaly (16).…”

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confidence: 99%

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Crystal Structure of an Affinity-matured Prolactin Complexed to Its Dimerized Receptor Reveals the Topology of Hormone Binding Site 2

Broutin

Jomain

Tallet

et al. 2010

Journal of Biological Chemistry

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We report the first crystal structure of a 1:2 hormone⅐receptor complex that involves prolactin (PRL) as the ligand, at 3.8-Å resolution. Stable ternary complexes were obtained by generating affinity-matured PRL variants harboring an N-terminal tail from ovine placental lactogen, a closely related PRL receptor (PRLR) ligand. This structure allows one to draw up an exhaustive inventory of the residues involved at the PRL⅐PRLR site 2 interface, consistent with all previously reported site-directed mutagenesis data. We propose, with this description, an interaction model involving three structural components of PRL site 2 ("three-pin plug"): the conserved glycine 129 of helix ␣3, the hydrogen bond network involving surrounding residues (glycine cavity), and the N terminus. The model provides a molecular basis for the properties of the different PRL analogs designed to date, including PRLR antagonists. Finally, comparison of our 1:2 PRL⅐PRLR 2 structure with those of free PRL and its 1:1 complex indicates that the structure of PRL undergoes significant changes when binding the first, but not the second receptor. This suggests that the second PRLR moiety adapts to the 1:1 complex rather than the opposite. In conclusion, this structure will be a useful guiding tool for further investigations of the molecular mechanisms involved in PRLR dimerization and activation, as well as for the optimization of PRLR antagonists, an emerging class of compounds with high therapeutic potential against breast and prostate cancer.

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confidence: 99%

“…PRL , it drags along the "lower part" of the hormone (regions [15][16][17][18][19][20][21][22][23][24][25][26][27][28] PRL and 125-136 PRL ). Region 15-28 PRL reaches its final position only when the second PRLR-ECD interacts at binding site 2.…”

mentioning

confidence: 99%

Crystal Structure of an Affinity-matured Prolactin Complexed to Its Dimerized Receptor Reveals the Topology of Hormone Binding Site 2

Broutin

Jomain

Tallet

et al. 2010

Journal of Biological Chemistry

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“…4). Mutational studies showed that replacing this Gly with several amino acids other than Ala resulted in an hGH antagonist (14). A subsequent report confirmed that replacing hGH G120 with arginine resulted in a GH antagonist (17).…”

Section: Gh As An Antagonist: the Role Of Gly-119 Substitutionmentioning

confidence: 93%

“…As with the triple-mutation analogue, all three of the single mutated analogues bound to the GHR with similar affinities. However, it was only when the G119 residue was substituted (bGH-G119R) that a dwarf transgenic mouse was produced (14). Thus functional antagonism of the GHR in the 3 D bGH analogue was determined by the amino acid in the G119R mutation.…”

Section: Structure -Function Relationship Of Ghmentioning

confidence: 99%

“…In the co-crystal Figure 4 Space-filling models of GH and the mutated GH antagonist, showing the cleft that occurs naturally in the third a-helix of GH because of the presence of Gly, and the same cleft filled in the GH antagonist by an amino acid with a large side group. (Reprinted, with permission, from (14).) structure of the GH -receptor complex, the cleft in the third a-helix interacts with a Trp residue in the GHR molecule (Trp-104).…”

Section: Gh As An Antagonist: the Role Of Gly-119 Substitutionmentioning

confidence: 99%

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Discovery and mechanism of action of pegvisomant

Kopchick

2003

Eur J Endocrinol

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Using a structure -function approach to the understanding of the molecular topology of the GH molecule, we discovered that glycine in the third a-helix of GH (G119 of bovine GH and G120 of human GH) was an important amino acid required for GH action. Substitution of this glycine residue with a variety of amino acids results in molecules that lack growth-promoting activity. More importantly, these molecules inhibit the actions of GH both in vitro and in vivo. These results, obtained more than a decade ago, were the basis for the discovery of GH antagonists. Since that time, efforts have been focused on establishing the mechanism by which these antagonists inhibit GH action. In this regard, in vivo expression of GH-antagonist genes in transgenic mice results in dwarf animals. The animals are fertile and possess no abnormal 'phenotypes'. Dwarf mice have also been created by disrupting or 'knocking out' the GH receptor gene. Together, these results have laid the foundation for the clinical use of GH antagonists when endogenous GH levels are increased or when GH is known to be a factor in the progression of the disorder.

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Impact of Growth Hormone on Regulation of Adipose Tissue

Troike

Henry

Jensen

et al. 2017

Comprehensive Physiology

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Increasing prevalence of obesity and obesity-related conditions worldwide has necessitated a more thorough understanding of adipose tissue (AT) and expanded the scope of research in this field. AT is now understood to be far more complex and dynamic than previously thought, which has also fueled research to reevaluate how hormones, such as growth hormone (GH), alter the tissue. In this review, we will introduce properties of AT important for understanding how GH alters the tissue, such as anatomical location of depots and adipokine output. We will provide an overview of GH structure and function and define several human conditions and cognate mouse lines with extremes in GH action that have helped shape our understanding of GH and AT. A detailed discussion of the GH/AT relationship will be included that addresses adipokine production, immune cell populations, lipid metabolism, senescence, differentiation, and fibrosis, as well as brown AT and beiging of white AT. A brief overview of how GH levels are altered in an obese state, and the efficacy of GH as a therapeutic option to manage obesity will be given. As we will reveal, the effects of GH on AT are numerous, dynamic and depot-dependent. © 2017 American Physiological Society. Compr Physiol 7:819-840, 2017.

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Glycine 119 of Bovine Growth Hormone is Critical for Growth-Promoting Activity

Cited by 163 publications

References 45 publications

Crystal Structure of an Affinity-matured Prolactin Complexed to Its Dimerized Receptor Reveals the Topology of Hormone Binding Site 2

Crystal Structure of an Affinity-matured Prolactin Complexed to Its Dimerized Receptor Reveals the Topology of Hormone Binding Site 2

Discovery and mechanism of action of pegvisomant

Impact of Growth Hormone on Regulation of Adipose Tissue

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