Crystal structure of human chorionic gonadotropin

Lapthorn, A.J.; Harris, D. C.; Littlejohn, Allison; Lustbader, Joyce W.; Canfield, Robert E.; Machin, K.J.; Morgan, Francis J.; Isaacs, Neil W.

doi:10.1038/369455a0

Cited by 884 publications

(622 citation statements)

References 44 publications

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“…The core of the subunit consists of three disulfide bridges forming a knot-like structure (Schlunegger & Grutter, 1992). Together with nerve growth factor, platelet-derived growth factor (Murray-Rust et al, 1993), and chorionic gonadotropin (Lapthorn et al, 1994), TGF-03 belongs to the class of cysteine-knot proteins. The disulfide bridges Cys 44-Cys 109 and Cys 48-Cys 11 1 form a ring wide enough for the disulfide bridge Cys 15-Cys 78 to pass through ( Fig.…”

Section: Resultsmentioning

confidence: 99%

The crystal structure of TGF‐β3 and comparison to TGF‐β2: Implications for receptor binding

et al. 1996

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Transforming growth factors /? belong to a group of cytokines that control cellular proliferation and differentiation. Five isoforms are known that share approximately 75% sequence identity, but exert different biological activities. The structure of TGF-/?3 was solved by X-ray crystallography and refined to a final R-factor of 17.5% at 2.0 A resolution. Comp~ison with the structure of TGF-02 (Schlunegger MP, Grutter MG, 1992, Nature 358430-434; Daopin S, Piez KA, Ogawa Y, Davies DR, 1992, Science 252369-373) reveals a virtually identical central core. Differences exist in the conformations of the N-terminal a-helix and in the P-sheet loops. In TGF-03, the N-terminal cu-helix has moved = 1 A away from the central core. This movement can be correlated with the mutation of Leu 17 to Val and Ala 47. to Pro in TGF-63. The /?-sheet loops rotate as a rigid body 9" around an axis that runs approximately parallel to the dimer axis. If these differences are recognized by the TGF-0 receptors, they might account for the individual cellular responses. A molecule of the precipitating agent dioxane is bound in a crystal contact, forming a hydrogen bond with Trp 32. This dioxane may occupy a carbohydrate-binding site, because dioxane possesses some structural similarity with a carbohydrate. The dioxane is in contact with two tryptophans, which are often involved in carbohydrate recognition.

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Section: Resultsmentioning

confidence: 99%

The crystal structure of TGF‐β3 and comparison to TGF‐β2: Implications for receptor binding

et al. 1996

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“…With an available crystal structure of hCG (Lapthorn et al, 1994;Wu et al, 1994;Tegoni et al, 1999), a reasonable working model of the LHR-ECD, coupled with considerable experimental structure-function data, primarily from site-directed mutagenesis, on both the hormone and receptor (Puett and Narayan, 2000;Zeng et al, 2001;Song et al, 2001a,b;Fanelli and Puett, 2002;Vischer et al, 2003a,b;Smits et al, 2003;Vassart et al, 2004), an attempt was made to generate plausible structures for the hCG-LHR-ECD complex. The 3D DOCK program (Gabb et al, 1997) was utilized for rigid-body docking; the structures were then ranked by an evaluation based on electrostatic interactions and geometrical fit, and finally the structures were filtered using several criteria for distance restraints, e.g.…”

Section: The Lhr-ecd: Structure and Hormone Bindingmentioning

confidence: 99%

A functional transmembrane complex: The luteinizing hormone receptor with bound ligand and G protein

Puett

DeMars

et al. 2007

Molecular and Cellular Endocrinology

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The luteinizing hormone receptor (LHR) is one of eight members in a cluster of the rhodopsin family of the large G protein-coupled receptor (GPCR) superfamily that contains some 800-900 genes in the human genome. LHR, along with its paralogons, follicle stimulating hormone receptor (FSHR) and thyroid stimulating hormone receptor, form one of the three classes in this cluster; the two other classes contain the relaxin-binding GPCRs and orphan GPCRs. These GPCRs are characterized by a relatively large ectodomain (ECD) containing leucine-rich-repeats (LRRs); in the class of glycoprotein hormone receptors, the LRR region is capped by N-terminal and C-terminal cysteinerich regions. Binding of human chorionic gonadotropin (hCG) or luteinizing hormone to the LHR-ECD triggers a conformational change of the transmembrane region of the receptor facilitating binding and activation of Gs, followed by effector enzyme activation and subsequent intracellular signaling. Viewing LHR as a transmembrane anchoring protein that sequentially binds hCG and Gs to give the hCG-LHR-Gs complex, numerous interactions and conformational changes must be considered. There is, unfortunately, a paucity of structural data on LHR, but crystal structures exist for hCG, the homologous FSH-FSHR-ECD (N-terminal fragment) complex, rhodopsin (in the inactive state), an active form of Gαs (transducin), and the βγ heterodimer. Using a combined experimental (site-directed mutagenesis followed by characterization in transfected cells) and computational (homology modeling and molecular dynamics simulations) approach, good working models are being developed for the protein-protein interaction faces and, in some cases, the ensuing conformational changes induced by complex formation. hCG binding to the LHR-ECD appears to involve several LRRs; LHR activation can be described in terms of disrupting a network of H-bonds in the cytosolic halves of helices 1-3, 6, and 7; and binding of LHR to Gs involves, in large part, intracellular loop 2 binding, presumably to Gsα at its C-terminus. Major gaps exist in our understanding at the molecular level of the six-polypeptide chain complex, hCG-LHR-Gs, but considerable progress has been made in the past few years.

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“…Two potential N-linked glycosylation sites, at positions 56 and 82 of the mature protein, were identified in squirrel monkey and owl monkey glycoprotein hormone α-subunits using the NetNGlyc 1.0 Server on-line program (http://www.cbs.dtu.dk/services/NetNGlyc/). The N-linked glycosylation sites as well as ten cysteine residues involved in disulfide bridge formation (Lapthorn et al, 1994) are conserved across all species examined. Also relatively well conserved is the sequence PLRSKK (positions 40−45 of human α-glycopeptide) that serves as a recognition marker for addition of Nacetylgalactosamine sulfate to oligosaccharides (Mengeling et al, 1995).…”

Section: Resultsmentioning

confidence: 99%

Molecular cloning of pituitary glycoprotein α-subunit and follicle stimulating hormone and chorionic gonadotropin β-subunits from New World squirrel monkey and owl monkey

Scammell

Funkhouser

Moyer

et al. 2008

General and Comparative Endocrinology

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The goal of this study was to characterize the gonadotropins expressed in pituitary glands of the New World squirrel monkey (Saimiri sp.) and owl monkey (Aotus sp.). The various subunits were amplified from total RNA from squirrel monkey and owl monkey pituitary glands by reverse transcription-polymerase chain reaction and the deduced amino acid sequences compared to those of other species. Mature squirrel monkey and owl monkey glycoprotein hormone α-polypeptides (96 amino acids in length) were determined to be 80% homologous to the human sequence. The sequences of mature β subunits of follicle stimulating hormone (FSHβ) from squirrel monkey and owl monkey (111 amino acids in length) are 92% homologous to human FSHβ. New World primate glycoprotein hormone α-polypeptides and FSHβ subunits showed conservation of all cysteine residues and consensus N-linked glycosylation sites. Attempts to amplify the β-subunit of luteinizing hormone from squirrel monkey and owl monkey pituitary glands were unsuccessful. Rather, the β-subunit of chorionic gonadotropin (CG) was amplified from pituitaries of both New World primates. Squirrel monkey and owl monkey CGβ are 143 and 144 amino acids in length and 77% homologous with human CGβ. The greatest divergence is in the C terminus, where all four sites for O-linked glycosylation in human CGβ, responsible for delayed metabolic clearance, are predicted to be absent in New World primate CGβs. It is likely that CG secreted from pituitary of New World primates exhibits a relatively short half-life compared to human CG.

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Crystal structure of human chorionic gonadotropin

Cited by 884 publications

References 44 publications

The crystal structure of TGF‐β3 and comparison to TGF‐β2: Implications for receptor binding

The crystal structure of TGF‐β3 and comparison to TGF‐β2: Implications for receptor binding

A functional transmembrane complex: The luteinizing hormone receptor with bound ligand and G protein

Molecular cloning of pituitary glycoprotein α-subunit and follicle stimulating hormone and chorionic gonadotropin β-subunits from New World squirrel monkey and owl monkey

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