Regulation of the oncoprotein Smoothened by small molecules

This Perspective discusses recent advances in understanding the structural and pharmacological properties of the downstream Hedgehog pathway effector Smoothened. Small molecule agonists and antagonists of Smo could be used as potential therapeutics. The Hedgehog pathway is critical for animal develo...

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Published inNature chemical biology Vol. 11; no. 4; pp. 246 - 255
Main Authors Sharpe, Hayley J, Wang, Weiru, Hannoush, Rami N, de Sauvage, Frederic J
Format Journal Article
LanguageEnglish
Published New York Nature Publishing Group US 01.04.2015
Nature Publishing Group
Subjects
631/136
631/67/1059
631/80/86
631/92/613
Allosteric Site
Amino Acid Sequence
Animals
Biochemical Engineering
Biochemistry
Bioorganic Chemistry
Cell Biology
Cell Membrane - metabolism
Chemistry
Chemistry/Food Science
Drosophila
Gene Expression Regulation
Gene Expression Regulation, Neoplastic
Humans
Ligands
Mice
Molecular biology
Molecular Conformation
Molecular Sequence Data
Mutation
Neoplasms - genetics
Neoplasms - metabolism
Patched Receptors
perspective
Protein Binding
Protein expression
Protein Structure, Tertiary
Receptors, Cell Surface - genetics
Receptors, G-Protein-Coupled - genetics
Receptors, G-Protein-Coupled - metabolism
Sequence Homology, Amino Acid
Signal transduction
Smoothened Receptor
Sterols - chemistry
Veratrum Alkaloids - chemistry
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Abstract This Perspective discusses recent advances in understanding the structural and pharmacological properties of the downstream Hedgehog pathway effector Smoothened. Small molecule agonists and antagonists of Smo could be used as potential therapeutics. The Hedgehog pathway is critical for animal development and has been implicated in multiple human malignancies. Despite great interest in targeting the pathway pharmacologically, many of the principles underlying the signal transduction cascade remain poorly understood. Hedgehog ligands are recognized by a unique receptor system that features the transporter-like protein Patched and the G protein–coupled receptor (GPCR)-like Smoothened (SMO). The biochemical interaction between these transmembrane proteins is the subject of intensive efforts. Recent structural and functional studies have provided great insight into the small-molecule regulation of SMO through identification of two distinct ligand-binding sites. In this Perspective, we review these recent findings and relate them to potential mechanisms for the endogenous regulation of SMO.
AbstractList This Perspective discusses recent advances in understanding the structural and pharmacological properties of the downstream Hedgehog pathway effector Smoothened. Small molecule agonists and antagonists of Smo could be used as potential therapeutics.
This Perspective discusses recent advances in understanding the structural and pharmacological properties of the downstream Hedgehog pathway effector Smoothened. Small molecule agonists and antagonists of Smo could be used as potential therapeutics. The Hedgehog pathway is critical for animal development and has been implicated in multiple human malignancies. Despite great interest in targeting the pathway pharmacologically, many of the principles underlying the signal transduction cascade remain poorly understood. Hedgehog ligands are recognized by a unique receptor system that features the transporter-like protein Patched and the G protein–coupled receptor (GPCR)-like Smoothened (SMO). The biochemical interaction between these transmembrane proteins is the subject of intensive efforts. Recent structural and functional studies have provided great insight into the small-molecule regulation of SMO through identification of two distinct ligand-binding sites. In this Perspective, we review these recent findings and relate them to potential mechanisms for the endogenous regulation of SMO.
The Hedgehog pathway is critical for animal development and has been implicated in multiple human malignancies. Despite great interest in targeting the pathway pharmacologically, many of the principles underlying the signal transduction cascade remain poorly understood. Hedgehog ligands are recognized by a unique receptor system that features the transporter-like protein Patched and the G protein-coupled receptor (GPCR)-like Smoothened (SMO). The biochemical interaction between these transmembrane proteins is the subject of intensive efforts. Recent structural and functional studies have provided great insight into the small-molecule regulation of SMO through identification of two distinct ligand-binding sites. In this Perspective, we review these recent findings and relate them to potential mechanisms for the endogenous regulation of SMO.
The Hedgehog pathway is critical for animal development and has been implicated in multiple human malignancies. Despite great interest in targeting the pathway pharmacologically, many of the principles underlying the signal transduction cascade remain poorly understood. Hedgehog ligands are recognized by a unique receptor system that features the transporter-like protein Patched and the G protein-coupled receptor (GPCR)-like Smoothened (SMO). The biochemical interaction between these transmembrane proteins is the subject of intensive efforts. Recent structural and functional studies have provided great insight into the small-molecule regulation of SMO through identification of two distinct ligand-binding sites. In this Perspective, we review these recent findings and relate them to potential mechanisms for the endogenous regulation of SMO.The Hedgehog pathway is critical for animal development and has been implicated in multiple human malignancies. Despite great interest in targeting the pathway pharmacologically, many of the principles underlying the signal transduction cascade remain poorly understood. Hedgehog ligands are recognized by a unique receptor system that features the transporter-like protein Patched and the G protein-coupled receptor (GPCR)-like Smoothened (SMO). The biochemical interaction between these transmembrane proteins is the subject of intensive efforts. Recent structural and functional studies have provided great insight into the small-molecule regulation of SMO through identification of two distinct ligand-binding sites. In this Perspective, we review these recent findings and relate them to potential mechanisms for the endogenous regulation of SMO.
Author de Sauvage, Frederic J
Wang, Weiru
Sharpe, Hayley J
Hannoush, Rami N
Author_xml – sequence: 1
  givenname: Hayley J
  surname: Sharpe
  fullname: Sharpe, Hayley J
  organization: Department of Molecular Oncology, Genentech Inc
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  givenname: Weiru
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  givenname: Rami N
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  givenname: Frederic J
  surname: de Sauvage
  fullname: de Sauvage, Frederic J
  email: sauvage@gene.com
  organization: Department of Molecular Oncology, Genentech Inc
BackLink https://www.ncbi.nlm.nih.gov/pubmed/25785427$$D View this record in MEDLINE/PubMed
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ProviderPackageCode CITATION
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PublicationCentury 2000
PublicationDate 2015-04-01
PublicationDateYYYYMMDD 2015-04-01
PublicationDate_xml – month: 04
  year: 2015
  text: 2015-04-01
  day: 01
PublicationDecade 2010
PublicationPlace New York
PublicationPlace_xml – name: New York
– name: United States
– name: Cambridge
PublicationTitle Nature chemical biology
PublicationTitleAbbrev Nat Chem Biol
PublicationTitleAlternate Nat Chem Biol
PublicationYear 2015
Publisher Nature Publishing Group US
Nature Publishing Group
Publisher_xml – name: Nature Publishing Group US
– name: Nature Publishing Group
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Snippet This Perspective discusses recent advances in understanding the structural and pharmacological properties of the downstream Hedgehog pathway effector...
The Hedgehog pathway is critical for animal development and has been implicated in multiple human malignancies. Despite great interest in targeting the pathway...
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crossref
springer
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StartPage 246
SubjectTerms 631/136
631/67/1059
631/80/86
631/92/613
Allosteric Site
Amino Acid Sequence
Animals
Biochemical Engineering
Biochemistry
Bioorganic Chemistry
Cell Biology
Cell Membrane - metabolism
Chemistry
Chemistry/Food Science
Drosophila
Gene Expression Regulation
Gene Expression Regulation, Neoplastic
Humans
Ligands
Mice
Molecular biology
Molecular Conformation
Molecular Sequence Data
Mutation
Neoplasms - genetics
Neoplasms - metabolism
Patched Receptors
perspective
Protein Binding
Protein expression
Protein Structure, Tertiary
Receptors, Cell Surface - genetics
Receptors, G-Protein-Coupled - genetics
Receptors, G-Protein-Coupled - metabolism
Sequence Homology, Amino Acid
Signal transduction
Smoothened Receptor
Sterols - chemistry
Veratrum Alkaloids - chemistry
Title Regulation of the oncoprotein Smoothened by small molecules
URI https://link.springer.com/article/10.1038/nchembio.1776
https://www.ncbi.nlm.nih.gov/pubmed/25785427
https://www.proquest.com/docview/1667698361
https://www.proquest.com/docview/1665121501
https://www.proquest.com/docview/1687674966
Volume 11
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