Abstract:
:The class Frizzled (FZD) or class F of G protein-coupled receptors consists of 10 FZD paralogues and Smoothened (SMO). FZDs coordinate wingless/Int-1 signaling and SMO mediates Hedgehog signaling. Class F receptor signaling is intrinsically important for embryonic development and its dysregulation leads to diseases, including diverse forms of tumors. With regard to the importance of class F signaling in human disease, these receptors provide an attractive target for therapeutics, exemplified by the use of SMO antagonists for the treatment of basal cell carcinoma. Here, we review recent structural insights in combination with a more detailed functional understanding of class F receptor activation, G protein coupling, conformation-based functional selectivity, and mechanistic details of activating cancer mutations, which will lay the basis for further development of class F-targeting small molecules for human therapy. SIGNIFICANCE STATEMENT: Stimulated by recent insights into the activation mechanisms of class F receptors from structural and functional analysis of Frizzled and Smoothened, we aim to summarize what we know about the molecular details of ligand binding, agonist-driven conformational changes, and class F receptor activation. A better understanding of receptor activation mechanisms will allow us to engage in structure- and mechanism-driven drug discovery with the potential to develop more isoform-selective and potentially pathway-selective drugs for human therapy.
journal_name
Mol Pharmacoljournal_title
Molecular pharmacologyauthors
Kozielewicz P,Turku A,Schulte Gdoi
10.1124/mol.119.117986subject
Has Abstractpub_date
2020-02-01 00:00:00pages
62-71issue
2eissn
0026-895Xissn
1521-0111pii
mol.119.117986journal_volume
97pub_type
杂志文章,评审abstract::There is no approved means to prevent the toxic actions of cocaine. Cocaine esterase (CocE) is found in a rhodococcal strain of bacteria that grows in the rhizosphere soil around the coca plant and has been found to hydrolyze cocaine in vitro. The esteratic activity of CocE (0.1-1.0 mg, i.v.) was characterized and con...
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journal_title:Molecular pharmacology
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pub_type: 杂志文章
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journal_title:Molecular pharmacology
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更新日期:2000-10-01 00:00:00
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journal_title:Molecular pharmacology
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doi:
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journal_title:Molecular pharmacology
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journal_title:Molecular pharmacology
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journal_title:Molecular pharmacology
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journal_title:Molecular pharmacology
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