Conformational plasticity of the ULK3 kinase domain.

Aniline Compounds / metabolism Benzamides / metabolism Biocatalysis / drug effects Catalytic Domain Humans Models, Molecular Nitriles / metabolism Oncogene Proteins / chemistry Protein Binding Protein Conformation Protein Domains Protein Kinase Inhibitors / metabolism Protein Serine-Threonine Kinases / chemistry Pyrimidines / metabolism Quinolines / metabolism Recombinant Proteins / chemistry Substrate Specificity
ULK kinase conformational changes enzyme–substrate interactions phosphorylation small-molecule inhibitor

Journal

The Biochemical journal
ISSN: 1470-8728
Titre abrégé: Biochem J
Pays: England
ID NLM: 2984726R

Informations de publication

Date de publication:
30 07 2021
Historique:
received: 09 04 2021
revised: 25 06 2021
accepted: 30 06 2021
pubmed: 1 7 2021
medline: 30 11 2021
entrez: 30 6 2021
Statut: ppublish

Résumé

The human protein kinase ULK3 regulates the timing of membrane abscission, thus being involved in exosome budding and cytokinesis. Herein, we present the first high-resolution structures of the ULK3 kinase domain. Its unique features are explored against the background of other ULK kinases. An inhibitor fingerprint indicates that ULK3 is highly druggable and capable of adopting a wide range of conformations. In accordance with this, we describe a conformational switch between the active and an inactive ULK3 conformation, controlled by the properties of the attached small-molecule binder. Finally, we discuss a potential substrate-recognition mechanism of the full-length ULK3 protein.

Identifiants

DOI: 10.1042/BCJ20210257 PMID: 34190988
pubmed: 34190988
pii: 229130
doi: 10.1042/BCJ20210257
doi:

Substances chimiques

Aniline Compounds 0
Benzamides 0
IST1 protein, human 0
Nitriles 0
Oncogene Proteins 0
Protein Kinase Inhibitors 0
Pyrimidines 0
Quinolines 0
Recombinant Proteins 0
bosutinib 5018V4AEZ0
N-(cyanomethyl)-4-(2-((4-(4-morpholinyl)phenyl)amino)-4-pyrimidinyl)benzamide 6O01GMS00P
Protein Serine-Threonine Kinases EC 2.7.11.1
ULK3 protein, human EC 2.7.11.1

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

2811-2823

Informations de copyright

© 2021 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.

Auteurs

Sebastian Mathea (S)

Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, 60438 Frankfurt, Germany.
Structural Genomics Consortium (SGC), Buchmann Institute for Life Sciences, Goethe-University Frankfurt, 60438 Frankfurt, Germany.
ORCID: 0000-0001-8500-4569

Eidarus Salah (E)

Structural Genomics Consortium (SGC), Nuffield Department of Medicine, University of Oxford, Oxford OX37DQ, U.K.
Target Discovery Institute (TDI), Centre for Medicines Discovery, Nuffield Department of Medicine, University of Oxford, Oxford OX37FZ, U.K.

Cynthia Tallant (C)

Structural Genomics Consortium (SGC), Nuffield Department of Medicine, University of Oxford, Oxford OX37DQ, U.K.
Target Discovery Institute (TDI), Centre for Medicines Discovery, Nuffield Department of Medicine, University of Oxford, Oxford OX37FZ, U.K.

Deep Chatterjee (D)

Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, 60438 Frankfurt, Germany.
Structural Genomics Consortium (SGC), Buchmann Institute for Life Sciences, Goethe-University Frankfurt, 60438 Frankfurt, Germany.

Benedict-Tilman Berger (BT)

Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, 60438 Frankfurt, Germany.
Structural Genomics Consortium (SGC), Buchmann Institute for Life Sciences, Goethe-University Frankfurt, 60438 Frankfurt, Germany.

Rebecca Konietzny (R)

Target Discovery Institute (TDI), Centre for Medicines Discovery, Nuffield Department of Medicine, University of Oxford, Oxford OX37FZ, U.K.

Susanne Müller (S)

Structural Genomics Consortium (SGC), Buchmann Institute for Life Sciences, Goethe-University Frankfurt, 60438 Frankfurt, Germany.

Benedikt M Kessler (BM)

Target Discovery Institute (TDI), Centre for Medicines Discovery, Nuffield Department of Medicine, University of Oxford, Oxford OX37FZ, U.K.

Stefan Knapp (S)

Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, 60438 Frankfurt, Germany.
Structural Genomics Consortium (SGC), Buchmann Institute for Life Sciences, Goethe-University Frankfurt, 60438 Frankfurt, Germany.
German Cancer Network (DKTK), Frankfurt/Mainz, 60438 Frankfurt, Germany.

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Classifications MeSH

questionsmedicales.fr › Composés chimiques organiques › Amines › Dérivés de l'aniline › Conformational plasticity of the ULK3 kinase domain.
questionsmedicales.fr › Composés chimiques organiques › Hydrocarbures › Hydrocarbures cycliques › Hydrocarbures aromatiques › Dérivés du benzène › Benzoates › Benzamides › Conformational plasticity of the ULK3 kinase domain.
questionsmedicales.fr › Métabolisme › Biocatalyse › Conformational plasticity of the ULK3 kinase domain.
questionsmedicales.fr › Phénomènes chimiques › Phénomènes biochimiques › Conformation moléculaire › Conformation des protéines › Éléments structuraux des protéines › Domaine catalytique › Conformational plasticity of the ULK3 kinase domain.
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Conformational plasticity of the ULK3 kinase domain.
questionsmedicales.fr › Techniques d'investigation › Modèles théoriques › Modèles moléculaires › Conformational plasticity of the ULK3 kinase domain.
questionsmedicales.fr › Composés chimiques organiques › Nitriles › Conformational plasticity of the ULK3 kinase domain.
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines tumorales › Protéines oncogènes › Conformational plasticity of the ULK3 kinase domain.
questionsmedicales.fr › Métabolisme › Liaison aux protéines › Conformational plasticity of the ULK3 kinase domain.
questionsmedicales.fr › Phénomènes chimiques › Phénomènes biochimiques › Conformation moléculaire › Conformation des protéines › Conformational plasticity of the ULK3 kinase domain.
questionsmedicales.fr › Phénomènes chimiques › Phénomènes biochimiques › Conformation moléculaire › Conformation des protéines › Structure tertiaire des protéines › Domaines protéiques › Conformational plasticity of the ULK3 kinase domain.
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Mécanismes moléculaires de l'action pharmacologique › Antienzymes › Inhibiteurs de protéines kinases › Conformational plasticity of the ULK3 kinase domain.
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Protein-Serine-Threonine Kinases › Conformational plasticity of the ULK3 kinase domain.
questionsmedicales.fr › Composés hétérocycliques › Composés hétéromonocycliques › Pyrimidines › Conformational plasticity of the ULK3 kinase domain.
questionsmedicales.fr › Composés hétérocycliques › Composés hétérocycliques à cycles fusionnés › Composés hétérobicycliques › Quinoléines › Conformational plasticity of the ULK3 kinase domain.
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines recombinantes › Conformational plasticity of the ULK3 kinase domain.
questionsmedicales.fr › Phénomènes chimiques › Phénomènes biochimiques › Spécificité du substrat › Conformational plasticity of the ULK3 kinase domain.