7REC

Structure of Thr354Asn, Glu355Gln, Thr412Asn, Ile414Met, Ile464His, and Phe467Met mutant human CaMKII alpha hub bound to 5-HDC

7REC の概要

• エントリーDOI: 10.2210/pdb7rec/pdb
• 分子名称: Calcium/calmodulin-dependent protein kinase type II subunit alpha, 5-hydroxydiclofenac, SODIUM ION, ... (4 entities in total)
• 機能のキーワード: camkii hub, oligomer, signaling protein
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 7
• 化学式量合計: 110756.92

構造登録者

McSpadden, E.D.,Chi, C.C.,Gee, C.L.,Kuriyan, J. (登録日: 2021-07-12, 公開日: 2021-07-21, 最終更新日: 2023-10-18)

主引用文献

Leurs, U.,Klein, A.B.,McSpadden, E.D.,Griem-Krey, N.,Solbak, S.M.O.,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.,Frolund, B.,Kornum, B.R.,van Woerden, G.M.,Clausen, R.P.,Kuriyan, J.,Clarkson, A.N.,Wellendorph, P.
GHB analogs confer neuroprotection through specific interaction with the CaMKII alpha hub domain.
Proc.Natl.Acad.Sci.USA, 118:-, 2021

PubMed Abstract: Ca/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.

PubMed: 34330837
DOI: 10.1073/pnas.2108079118

実験手法

X-RAY DIFFRACTION (2.2 Å)