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GHB analogs confer neuroprotection through specific interaction with the CaMKIIα hub domain.
Leurs, Ulrike; Klein, Anders B; McSpadden, Ethan D; Griem-Krey, Nane; Solbak, Sara M Ø; Houlton, Josh; Villumsen, Inge S; Vogensen, Stine B; Hamborg, Louise; Gauger, Stine J; Palmelund, Line B; Larsen, Anne Sofie G; Shehata, Mohamed A; Kelstrup, Christian D; Olsen, Jesper V; Bach, Anders; Burnie, Robert O; Kerr, D Steven; Gowing, Emma K; Teurlings, Selina M W; Chi, Chris C; Gee, Christine L; Frølund, Bente; Kornum, Birgitte R; van Woerden, Geeske M; Clausen, Rasmus P; Kuriyan, John; Clarkson, Andrew N; Wellendorph, Petrine.
Afiliação
  • Leurs U; Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2100 Copenhagen, Denmark.
  • Klein AB; Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2100 Copenhagen, Denmark.
  • McSpadden ED; HHMI, University of California, Berkeley, CA 94720.
  • Griem-Krey N; Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720.
  • Solbak SMØ; California Institute for Quantitative Biosciences, University of California, Berkeley, CA 94720.
  • Houlton J; Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2100 Copenhagen, Denmark.
  • Villumsen IS; Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2100 Copenhagen, Denmark.
  • Vogensen SB; Department of Anatomy, Brain Health Research Centre and Brain Research New Zealand, University of Otago, 9054 Dunedin, New Zealand.
  • Hamborg L; Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2100 Copenhagen, Denmark.
  • Gauger SJ; Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2100 Copenhagen, Denmark.
  • Palmelund LB; Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2100 Copenhagen, Denmark.
  • Larsen ASG; Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2100 Copenhagen, Denmark.
  • Shehata MA; Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2100 Copenhagen, Denmark.
  • Kelstrup CD; Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2100 Copenhagen, Denmark.
  • Olsen JV; Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2100 Copenhagen, Denmark.
  • Bach A; Proteomics Program, Faculty of Health and Medical Sciences, Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, DK-2200 Copenhagen, Denmark.
  • Burnie RO; Proteomics Program, Faculty of Health and Medical Sciences, Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, DK-2200 Copenhagen, Denmark.
  • Kerr DS; Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2100 Copenhagen, Denmark.
  • Gowing EK; Department of Anatomy, Brain Health Research Centre and Brain Research New Zealand, University of Otago, 9054 Dunedin, New Zealand.
  • Teurlings SMW; Department of Pharmacology and Toxicology, University of Otago, 9054 Dunedin, New Zealand.
  • Chi CC; Department of Anatomy, Brain Health Research Centre and Brain Research New Zealand, University of Otago, 9054 Dunedin, New Zealand.
  • Gee CL; Department of Neuroscience, Erasmus University Medical Center, 3015 GD, Rotterdam, The Netherlands.
  • Frølund B; HHMI, University of California, Berkeley, CA 94720.
  • Kornum BR; Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720.
  • van Woerden GM; California Institute for Quantitative Biosciences, University of California, Berkeley, CA 94720.
  • Clausen RP; HHMI, University of California, Berkeley, CA 94720.
  • Kuriyan J; Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720.
  • Clarkson AN; California Institute for Quantitative Biosciences, University of California, Berkeley, CA 94720.
  • Wellendorph P; Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2100 Copenhagen, Denmark.
Proc Natl Acad Sci U S A ; 118(31)2021 08 03.
Article em En | MEDLINE | ID: mdl-34330837
ABSTRACT
Ca2+/calmodulin-dependent protein kinase II alpha subunit (CaMKIIα) is a key neuronal signaling protein and an emerging drug target. The central hub domain regulates the activity of CaMKIIα by organizing the holoenzyme complex into functional oligomers, yet pharmacological modulation of the hub domain has never been demonstrated. Here, using a combination of photoaffinity labeling and chemical proteomics, we show that compounds related to the natural substance γ-hydroxybutyrate (GHB) bind selectively to CaMKIIα. By means of a 2.2-Å x-ray crystal structure of ligand-bound CaMKIIα hub, we reveal the molecular details of the binding site deep within the hub. Furthermore, we show that binding of GHB and related analogs to this site promotes concentration-dependent increases in hub thermal stability believed to alter holoenzyme functionality. Selectively under states of pathological CaMKIIα activation, hub ligands provide a significant and sustained neuroprotection, which is both time and dose dependent. This is demonstrated in neurons exposed to excitotoxicity and in a mouse model of cerebral ischemia with the selective GHB analog, HOCPCA (3-hydroxycyclopent-1-enecarboxylic acid). Together, our results indicate a hitherto unknown mechanism for neuroprotection by a highly specific and unforeseen interaction between the CaMKIIα hub domain and small molecule brain-penetrant GHB analogs. This establishes GHB analogs as powerful tools for investigating CaMKII neuropharmacology in general and as potential therapeutic compounds for cerebral ischemia in particular.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Oxibato de Sódio / Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina Limite: Humans Idioma: En Revista: Proc Natl Acad Sci U S A Ano de publicação: 2021 Tipo de documento: Article País de afiliação: Dinamarca
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Oxibato de Sódio / Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina Limite: Humans Idioma: En Revista: Proc Natl Acad Sci U S A Ano de publicação: 2021 Tipo de documento: Article País de afiliação: Dinamarca