Structural diversity of the epigenetics pocketome.
Identifieur interne : 000111 ( Main/Exploration ); précédent : 000110; suivant : 000112Structural diversity of the epigenetics pocketome.
Auteurs : Alexandre Cabaye [Canada] ; Kong T. Nguyen [Canada] ; Lihua Liu [Canada] ; Vineet Pande [Belgique] ; Matthieu Schapira [Canada]Source :
- Proteins [ 1097-0134 ] ; 2015.
English descriptors
- KwdEn :
- Acetyltransferases (antagonists & inhibitors), Acetyltransferases (chemistry), Acetyltransferases (genetics), Antineoplastic Agents (chemical synthesis), Antineoplastic Agents (chemistry), Antineoplastic Agents (pharmacology), Binding Sites, Chromatin (chemistry), Chromatin (drug effects), DNA, Neoplasm (antagonists & inhibitors), DNA, Neoplasm (chemistry), DNA, Neoplasm (genetics), Databases, Protein, Epigenesis, Genetic, Histones (antagonists & inhibitors), Histones (chemistry), Histones (genetics), Humans, Internet, Ligands, Models, Molecular, Neoplasm Proteins (antagonists & inhibitors), Neoplasm Proteins (chemistry), Neoplasm Proteins (genetics), Neoplasms (chemistry), Neoplasms (drug therapy), Neoplasms (genetics), Neoplasms (pathology), Protein Binding, Protein Processing, Post-Translational, Protein Structure, Tertiary, Protein-Arginine N-Methyltransferases (antagonists & inhibitors), Protein-Arginine N-Methyltransferases (chemistry), Protein-Arginine N-Methyltransferases (genetics), RNA, Neoplasm (antagonists & inhibitors), RNA, Neoplasm (chemistry), RNA, Neoplasm (genetics), Sirtuins (antagonists & inhibitors), Sirtuins (chemistry), Sirtuins (genetics), Small Molecule Libraries (chemical synthesis), Small Molecule Libraries (chemistry), Small Molecule Libraries (pharmacology), Software.
- MESH :
- chemical , antagonists & inhibitors : Acetyltransferases, DNA, Neoplasm, Histones, Neoplasm Proteins, Protein-Arginine N-Methyltransferases, RNA, Neoplasm, Sirtuins.
- chemical , chemical synthesis : Antineoplastic Agents, Small Molecule Libraries.
- chemical , chemistry : Acetyltransferases, Antineoplastic Agents, Chromatin, DNA, Neoplasm, Histones, Neoplasm Proteins, Protein-Arginine N-Methyltransferases, RNA, Neoplasm, Sirtuins, Small Molecule Libraries.
- chemical , drug effects : Chromatin.
- chemical , genetics : Acetyltransferases, DNA, Neoplasm, Histones, Neoplasm Proteins, Protein-Arginine N-Methyltransferases, RNA, Neoplasm, Sirtuins.
- chemical , pharmacology : Antineoplastic Agents, Small Molecule Libraries.
- chemistry : Neoplasms.
- drug therapy : Neoplasms.
- genetics : Neoplasms.
- pathology : Neoplasms.
- Binding Sites, Databases, Protein, Epigenesis, Genetic, Humans, Internet, Ligands, Models, Molecular, Protein Binding, Protein Processing, Post-Translational, Protein Structure, Tertiary, Software.
Abstract
Protein families involved in chromatin-templated events are emerging as novel target classes in oncology and other disease areas. The ability to discover selective inhibitors against chromatin factors depends on the presence of structural features that are unique to the targeted sites. To evaluate challenges and opportunities toward the development of selective inhibitors, we calculated all pair wise structural distances between 575 structures from the protein databank representing 163 unique binding pockets found in protein domains that write, read or erase post-translational modifications on histones, DNA, and RNA. We find that the structural similarity of binding sites does not always follow the sequence similarity of protein domains. Our analysis reveals increased risks of activity across target-class for compounds competing with the cofactor of protein arginine methyltransferases, lysine acetyltransferases, and sirtuins, while exploiting the conformational plasticity of a protein target is a path toward selective inhibition. The structural diversity landscape of the epigenetics pocketome can be explored via an open-access graphic user interface at thesgc.org/epigenetics_pocketome.
DOI: 10.1002/prot.24830
PubMed: 25974248
Affiliations:
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Le document en format XML
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Nguyen</name><affiliation wicri:level="4"><nlm:affiliation>Structural Genomics Consortium, University of Toronto, Toronto, Ontario, M5G 1L7, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Structural Genomics Consortium, University of Toronto, Toronto, Ontario, M5G 1L7</wicri:regionArea><orgName type="university">Université de Toronto</orgName><placeName><settlement type="city">Toronto</settlement><region type="state">Ontario</region></placeName></affiliation></author><author><name sortKey="Liu, Lihua" sort="Liu, Lihua" uniqKey="Liu L" first="Lihua" last="Liu">Lihua Liu</name><affiliation wicri:level="4"><nlm:affiliation>Structural Genomics Consortium, University of Toronto, Toronto, Ontario, M5G 1L7, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Structural Genomics Consortium, University of Toronto, Toronto, Ontario, M5G 1L7</wicri:regionArea><orgName type="university">Université de 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xml:lang="fr">Canada</country><wicri:regionArea>Structural Genomics Consortium, University of Toronto, Toronto, Ontario, M5G 1L7</wicri:regionArea><orgName type="university">Université de Toronto</orgName><placeName><settlement type="city">Toronto</settlement><region type="state">Ontario</region></placeName></affiliation></author></analytic><series><title level="j">Proteins</title><idno type="eISSN">1097-0134</idno><imprint><date when="2015" type="published">2015</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Acetyltransferases (antagonists & inhibitors)</term><term>Acetyltransferases (chemistry)</term><term>Acetyltransferases (genetics)</term><term>Antineoplastic Agents (chemical synthesis)</term><term>Antineoplastic Agents (chemistry)</term><term>Antineoplastic Agents (pharmacology)</term><term>Binding Sites</term><term>Chromatin (chemistry)</term><term>Chromatin (drug effects)</term><term>DNA, Neoplasm (antagonists & inhibitors)</term><term>DNA, Neoplasm (chemistry)</term><term>DNA, Neoplasm (genetics)</term><term>Databases, Protein</term><term>Epigenesis, Genetic</term><term>Histones (antagonists & inhibitors)</term><term>Histones (chemistry)</term><term>Histones (genetics)</term><term>Humans</term><term>Internet</term><term>Ligands</term><term>Models, Molecular</term><term>Neoplasm Proteins (antagonists & inhibitors)</term><term>Neoplasm Proteins (chemistry)</term><term>Neoplasm Proteins (genetics)</term><term>Neoplasms (chemistry)</term><term>Neoplasms (drug therapy)</term><term>Neoplasms (genetics)</term><term>Neoplasms (pathology)</term><term>Protein Binding</term><term>Protein Processing, Post-Translational</term><term>Protein Structure, Tertiary</term><term>Protein-Arginine N-Methyltransferases (antagonists & inhibitors)</term><term>Protein-Arginine N-Methyltransferases (chemistry)</term><term>Protein-Arginine N-Methyltransferases (genetics)</term><term>RNA, Neoplasm (antagonists & inhibitors)</term><term>RNA, Neoplasm (chemistry)</term><term>RNA, Neoplasm (genetics)</term><term>Sirtuins (antagonists & inhibitors)</term><term>Sirtuins (chemistry)</term><term>Sirtuins (genetics)</term><term>Small Molecule Libraries (chemical synthesis)</term><term>Small Molecule Libraries (chemistry)</term><term>Small Molecule Libraries (pharmacology)</term><term>Software</term></keywords><keywords scheme="MESH" type="chemical" qualifier="antagonists & inhibitors" xml:lang="en"><term>Acetyltransferases</term><term>DNA, Neoplasm</term><term>Histones</term><term>Neoplasm Proteins</term><term>Protein-Arginine N-Methyltransferases</term><term>RNA, Neoplasm</term><term>Sirtuins</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemical synthesis" xml:lang="en"><term>Antineoplastic Agents</term><term>Small Molecule Libraries</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Acetyltransferases</term><term>Antineoplastic Agents</term><term>Chromatin</term><term>DNA, Neoplasm</term><term>Histones</term><term>Neoplasm Proteins</term><term>Protein-Arginine N-Methyltransferases</term><term>RNA, Neoplasm</term><term>Sirtuins</term><term>Small Molecule Libraries</term></keywords><keywords scheme="MESH" type="chemical" qualifier="drug effects" xml:lang="en"><term>Chromatin</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Acetyltransferases</term><term>DNA, Neoplasm</term><term>Histones</term><term>Neoplasm Proteins</term><term>Protein-Arginine N-Methyltransferases</term><term>RNA, Neoplasm</term><term>Sirtuins</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Antineoplastic Agents</term><term>Small Molecule Libraries</term></keywords><keywords scheme="MESH" qualifier="chemistry" xml:lang="en"><term>Neoplasms</term></keywords><keywords scheme="MESH" qualifier="drug therapy" xml:lang="en"><term>Neoplasms</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Neoplasms</term></keywords><keywords scheme="MESH" qualifier="pathology" xml:lang="en"><term>Neoplasms</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Binding Sites</term><term>Databases, Protein</term><term>Epigenesis, Genetic</term><term>Humans</term><term>Internet</term><term>Ligands</term><term>Models, Molecular</term><term>Protein Binding</term><term>Protein Processing, Post-Translational</term><term>Protein Structure, Tertiary</term><term>Software</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Protein families involved in chromatin-templated events are emerging as novel target classes in oncology and other disease areas. The ability to discover selective inhibitors against chromatin factors depends on the presence of structural features that are unique to the targeted sites. To evaluate challenges and opportunities toward the development of selective inhibitors, we calculated all pair wise structural distances between 575 structures from the protein databank representing 163 unique binding pockets found in protein domains that write, read or erase post-translational modifications on histones, DNA, and RNA. We find that the structural similarity of binding sites does not always follow the sequence similarity of protein domains. Our analysis reveals increased risks of activity across target-class for compounds competing with the cofactor of protein arginine methyltransferases, lysine acetyltransferases, and sirtuins, while exploiting the conformational plasticity of a protein target is a path toward selective inhibition. The structural diversity landscape of the epigenetics pocketome can be explored via an open-access graphic user interface at thesgc.org/epigenetics_pocketome.</div></front></TEI><affiliations><list><country><li>Belgique</li><li>Canada</li></country><region><li>Ontario</li></region><settlement><li>Toronto</li></settlement><orgName><li>Université de Toronto</li></orgName></list><tree><country name="Canada"><region name="Ontario"><name sortKey="Cabaye, Alexandre" sort="Cabaye, Alexandre" uniqKey="Cabaye A" first="Alexandre" last="Cabaye">Alexandre Cabaye</name></region><name sortKey="Liu, Lihua" sort="Liu, Lihua" uniqKey="Liu L" first="Lihua" last="Liu">Lihua Liu</name><name sortKey="Nguyen, Kong T" sort="Nguyen, Kong T" uniqKey="Nguyen K" first="Kong T" last="Nguyen">Kong T. Nguyen</name><name sortKey="Schapira, Matthieu" sort="Schapira, Matthieu" uniqKey="Schapira M" first="Matthieu" last="Schapira">Matthieu Schapira</name></country><country name="Belgique"><noRegion><name sortKey="Pande, Vineet" sort="Pande, Vineet" uniqKey="Pande V" first="Vineet" last="Pande">Vineet Pande</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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