气候变化领域集成服务门户(CCPortal): GHB analogs confer neuroprotection through specific interaction with the CaMKIIα hub domain

CCPortal

DOI	10.1073/pnas.2108079118
	GHB analogs confer neuroprotection through specific interaction with the CaMKIIα hub domain
	Leurs U.; Klein A.B.; McSpadden E.D.; Griem-Krey N.; Solbak S.M.Ø.; Houlton J.; Villumsen I.S.; Vogensen S.B.; Hamborg L.; Gauger S.J.; Palmelund L.B.; Larsen A.S.G.; Shehata M.A.; Kelstrup C.D.; Olsen J.V.; Bach A.; Burnie R.O.; Kerr D.S.; Gowing E.K.; Teurlings S.M.W.; Chi C.C.; Gee C.L.; Frølund B.; Kornum B.R.; van Woerden G.M.; Clausen R.P.; Kuriyan J.; Clarkson A.N.; Wellendorph P.
发表日期	2021
ISSN	0027-8424
卷号	118 期号:31
英文摘要	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-ene-carboxylic 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. © This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND).
英文关键词	Excitotoxicity; HOCPCA; Photoaffinity labeling; Photothrombotic stroke; X-ray crystallography
语种	英语
scopus关键词	3 hydroxycyclopent 1 enecarboxylic acid; 4 hydroxybutyric acid; calcium calmodulin dependent protein kinase 2 alpha; calcium calmodulin dependent protein kinase II; unclassified drug; 3-hydroxycyclopent-1-enecarboxylic acid; calcium calmodulin dependent protein kinase II; carboxylic acid; cyclopentane derivative; oxybate sodium; protein binding; animal experiment; animal model; animal tissue; Article; binding site; brain ischemia; controlled study; crystal structure; drug structure; enzyme activation; excitotoxicity; female; male; mouse; nerve cell; neuroprotection; nonhuman; photoaffinity labeling; protein protein interaction; single drug dose; thermostability; drug effect; gene expression regulation; genetics; HEK293 cell line; human; metabolism; neuroprotection; protein domain; signal transduction; X ray crystallography; Binding Sites; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Carboxylic Acids; Crystallography, X-Ray; Cyclopentanes; Gene Expression Regulation, Enzymologic; HEK293 Cells; Humans; Neuroprotection; Protein Binding; Protein Domains; Signal Transduction; Sodium Oxybate
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/251081
作者单位	Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, DK-2100, Denmark; HHMI, University of California, Berkeley, CA 94720, United States; Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720, United States; California Institute for Quantitative Biosciences, University of California, Berkeley, CA 94720, United States; Department of Anatomy, Brain Health Research Centre and Brain Research New Zealand, University of Otago, Dunedin, 9054, New Zealand; Proteomics Program, Faculty of Health and Medical Sciences, Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Copenhagen, DK-2200, Denmark; Department of Pharmacology and Toxicology, University of Otago, Dunedin, 9054, New Zealand; Department of Neuroscience, Erasmus University Medical Center, Rotterdam, 3015 GD, Netherlands; Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen,...
推荐引用方式 GB/T 7714	Leurs U.,Klein A.B.,McSpadden E.D.,et al. GHB analogs confer neuroprotection through specific interaction with the CaMKIIα hub domain[J],2021,118(31).
APA	Leurs U..,Klein A.B..,McSpadden E.D..,Griem-Krey N..,Solbak S.M.Ø..,...&Wellendorph P..(2021).GHB analogs confer neuroprotection through specific interaction with the CaMKIIα hub domain.Proceedings of the National Academy of Sciences of the United States of America,118(31).
MLA	Leurs U.,et al."GHB analogs confer neuroprotection through specific interaction with the CaMKIIα hub domain".Proceedings of the National Academy of Sciences of the United States of America 118.31(2021).