Evaluation of Small-Molecule Modulators of the Luteinizing Hormone/Choriogonadotropin and Thyroid Stimulating Hormone Receptors:  Structure−Activity Relationships and Selective Binding Patterns

Moore, Susanna; Jaeschke, Holger; Kleinau, Gunnar; Neumann, Susanne; Costanzi, Stefano; Jiang, Jian‐kang; Childress, John; Raaka, Bruce M.; Colson, Anny‐Odile; Paschke, Ralf; Krause, Gerd; Thomas, Craig J.; Gershengorn, Marvin C.

doi:10.1021/jm060247s

Cited by 81 publications

(54 citation statements)

References 18 publications

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“…Based on this prototype, also the more potent Org 42599 was developed (18). In contrast to glycoprotein hormones hCG and LH, Org 41841 does not bind to the ECD of the receptor, but directly to the 7TMD (17,19,20). In this study we exploited this feature to study the functional intactness of the mutant LH receptor proteins, i.e.…”

Section: Discussionmentioning

confidence: 99%

“…1A). Org 42599 is a low molecular weight LH receptor agonist, based on lead optimization of Org 41841 (18) and, as Org 41841 binds to and activates the receptor directly at the 7TMD (17,19,20), and does not require the ECD. It should be noted that, compared with WT, not only the maximal effect, but also the potency of Org 42599 was reduced (supplemental materials Fig.…”

Section: Constellation Of Disulfide Bridges In the Ccr-despitementioning

confidence: 99%

“…Org 41841 and Org 42599) were characterized as a novel class of low molecular weight LH receptor agonists (17,18). These ligands can activate the receptor by interacting directly with the 7TMD, rather than with the receptor ectodomain (19,20).…”

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confidence: 99%

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Asp330 and Tyr331 in the C-terminal Cysteine-rich Region of the Luteinizing Hormone Receptor Are Key Residues in Hormone-induced Receptor Activation

Bruysters

Verhoef-Post

Themmen

2008

Journal of Biological Chemistry

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The luteinizing hormone (LH) receptor plays an essential role in male and female gonadal function. Together with the follicle-stimulating hormone (FSH) and thyroid stimulating hormone (TSH) receptors, the LH receptor forms the family of glycoprotein hormone receptors. All glycoprotein hormone receptors share a common modular topography, with an N-terminal extracellular ligand binding domain and a C-terminal seven-transmembrane transduction domain. The ligand binding domain consists of 9 leucine-rich repeats, flanked by N-and C-terminal cysteine-rich regions. Recently, crystal structures have been published of the extracellular domains of the FSH and TSH receptors. However, the C-terminal cysteine-rich region (CCR), also referred to as the "hinge region," was not included in these structures. Both structure and function of the CCR therefore remain unknown. In this study we set out to characterize important domains within the CCR of the LH receptor. First, we mutated all cysteines and combinations of cysteines in the CCR to identify the most probable disulfide bridges. Second, we exchanged large parts of the LH receptor CCR by its FSH receptor counterparts, and characterized the mutant receptors in transiently transfected HEK 293 cells. We zoomed in on important regions by focused exchange and deletion mutagenesis followed by alanine scanning. Mutations in the CCR specifically decreased the potencies of LH and hCG, because the potency of the low molecular weight agonist Org 41841 was unaffected. Using this unbiased approach, we identified Asp 330 and Tyr 331 as key amino acids in LH/hCG mediated signaling.The glycoprotein hormone luteinizing hormone (LH) 3 has an essential role in reproduction. In both sexes, LH regulates the production of gonadal androgens, which in women are almost completely converted to estrogens. Furthermore, in women the mid-cycle LH peak triggers ovulation of the mature oocyte ready to be fertilized, whereas the closely related pregnancy hormone, chorionic gonadotropin (hCG), supports the corpus luteum of pregnancy. Both LH and hCG act by binding and activating the LH receptor. The LH receptor has a modular architecture consisting of an ectodomain or extracellular hormone binding domain (ECD), linked to a seven-transmembrane signal transduction domain (7TMD). Together with the receptors for thyroid stimulating hormone (TSH) and follicle stimulating hormone (FSH), the LH receptor belongs to the glycoprotein hormone receptor family. The extracellular ligand binding domain of this family consists of a stretch of nine leucine-rich repeats (LRRs), flanked by N-terminal and C-terminal cysteine-rich clusters (NCR and CCR, respectively). The crystal structures that have been determined for major parts of FSHR and TSHR ECDs show that the LRRs are organized as ␤ sheets, and give rise to a curved helical tube of which the concave surface forms the hormone-binding surface (1, 2). The NCR provides an additional ␤ strand to the binding surface. Because the CCR was not included in the protein expression...

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Section: Discussionmentioning

confidence: 99%

Section: Constellation Of Disulfide Bridges In the Ccr-despitementioning

confidence: 99%

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Asp330 and Tyr331 in the C-terminal Cysteine-rich Region of the Luteinizing Hormone Receptor Are Key Residues in Hormone-induced Receptor Activation

Bruysters

Verhoef-Post

Themmen

2008

Journal of Biological Chemistry

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“…Путем его модификации был получен более ак-тивный аналог Org 43553, который до сих пор счита-ют «золотым стандартом» низкомолекулярных аго-нистов ЛГР [9,10]. Соединение Org 43553 с высокой аффинностью (K d , 2,4 нМ) связывалось с ЛГР; свя-зывание было специфичным и не выявлялось в от-ношении рецепторов ФСГ и ТТГ.…”

Section: активность тиенопиримидиновых производных In Vitrounclassified

Thienopyrimidines - the new class of low molecular weight regulators of the female reproductive system

Шпаков¹

2015

Probl Endokrinol (Mosk)

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Ключевую роль в функционировании гипотала-мо-гипофизарно-гонадной (ГГГ) оси играют рецеп-торы лютеинизирующего гормона (ЛГР), с которы-ми специфически связываются как ЛГ, так и его структурный и функциональный гомолог -хорио-нический гонадотропин человека (ХГЧ). Функцио-нально активный ЛГ представляет собой гетероди-мер с высококонсервативной α-субъединицей и ва-риабельной β-субъединицей, определяющей специ-фичность связывания с ЛГР. Практическое приме-нение ЛГ и ХГЧ ограничено необходимостью их парентерального введения, быстрым снижением чувствительности тканей-мишеней к ним, иммуно-генностью, высокой стоимостью. Одной из актуаль-ных задач современной эндокринологии является разработка новых регуляторов ЛГР, в том числе от-личающихся от ЛГ по механизму действия на ткани репродуктивной системы.ЛГР относится к семейству рецепторов серпан-тинного типа с семью трансмембранными домена-ми, пронизывающими плазматическую мембрану клетки [1][2][3]. Эти домены соединены между собой

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“…Его замена на аланин полностью блокирует связывание вещества Org41841 с рецептором ЛГ и активацию им АЦ. Предполагается, что боковая карбоксильная группа Glu образует водородную связь с аминогруппой низкомолекулярного лиганда, обеспечивая его эффективное связывание [26,28]. В 2007 г. были открыты производные пиразола, которые также являются агонистами рецептора ЛГ [29].…”

Section: рисунокunclassified

Low-molecular regulators of polypeptide hormones receptors containing LGR-repeats

Шпаков

Shpakova

2010

BIOMED KHIM

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During the last years the low-molecular non-peptidic regulators of the polypeptide hormones receptors containing LGR-repeats were identified. In the review the data on the structure and the molecular mechanisms of action of these regulators as agonists and antagonists of the luteinizing, follicle-stimulating and thyrotropin hormones are analyzed and systematized. The regulators interact with the serpentine domain of LGR-receptor and trigger the signaling cascades coupled with the receptor. Low-molecular agonists and antagonists of the LGR-receptors are considered as a new generation of the drugs that regulates the functional activity of sensitive to pituitary glycoprotein hormones signaling systems with high efficiency and selectivity. These regulators are more accessible compared to the hormones and can be use orally.

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Evaluation of Small-Molecule Modulators of the Luteinizing Hormone/Choriogonadotropin and Thyroid Stimulating Hormone Receptors: Structure−Activity Relationships and Selective Binding Patterns

Cited by 81 publications

References 18 publications

Asp330 and Tyr331 in the C-terminal Cysteine-rich Region of the Luteinizing Hormone Receptor Are Key Residues in Hormone-induced Receptor Activation

Asp330 and Tyr331 in the C-terminal Cysteine-rich Region of the Luteinizing Hormone Receptor Are Key Residues in Hormone-induced Receptor Activation

Thienopyrimidines - the new class of low molecular weight regulators of the female reproductive system

Low-molecular regulators of polypeptide hormones receptors containing LGR-repeats

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