GHB analogs confer neuroprotection through specific interaction with the CaMKIIα hub domain

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt

Standard

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.

I: Proceedings of the National Academy of Sciences of the United States of America, Bind 118, Nr. 31, e2108079118, 2021.

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt

Harvard

Leurs, U, Klein, AB, McSpadden, ED, Griem-Krey, N, Solbak, SMØ, Houlton, J, Villumsen, IS, Vogensen, SB, Hamborg, L, Gauger, SJ, Palmelund, LB, Larsen, ASG, Shehata, MA, Kelstrup, CD, Olsen, JV, Bach, A, Burnie, RO, Kerr, DS, Gowing, EK, Teurlings, SMW, Chi, CC, Gee, CL, Frølund, B, Kornum, BR, van Woerden, GM, Clausen, RP, Kuriyan, J, Clarkson, AN & 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, bind 118, nr. 31, e2108079118. https://doi.org/10.1073/pnas.2108079118

APA

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., ... 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), [e2108079118]. https://doi.org/10.1073/pnas.2108079118

Vancouver

Leurs U, Klein AB, McSpadden ED, Griem-Krey N, Solbak SMØ, Houlton J o.a. 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. 2021;118(31). e2108079118. https://doi.org/10.1073/pnas.2108079118

Author

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. / GHB analogs confer neuroprotection through specific interaction with the CaMKIIα hub domain. I: Proceedings of the National Academy of Sciences of the United States of America. 2021 ; Bind 118, Nr. 31.

Bibtex

@article{0ddca2307d0d46e1bba7ffc5b80ed73d,
title = "GHB analogs confer neuroprotection through specific interaction with the CaMKIIα hub domain",
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-{\AA} 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.",
author = "Ulrike Leurs and Klein, {Anders B.} and McSpadden, {Ethan D} and Nane Griem-Krey and Solbak, {Sara M {\O}} and Josh Houlton and Villumsen, {Inge S} and Vogensen, {Stine B} and Louise Hamborg and Gauger, {Stine J} and Palmelund, {Line B} and Larsen, {Anne Sofie G.} and Shehata, {Mohamed A} and Kelstrup, {Christian D} and Olsen, {Jesper V} and Anders Bach and Burnie, {Robert O} and Kerr, {D Steven} and Gowing, {Emma K} and Teurlings, {Selina M W} and Chi, {Chris C} and Gee, {Christine L} and Bente Fr{\o}lund and Kornum, {Birgitte R} and {van Woerden}, {Geeske M} and Clausen, {Rasmus P} and John Kuriyan and Clarkson, {Andrew N} and Petrine Wellendorph",
note = "Copyright {\textcopyright} 2021 the Author(s). Published by PNAS.",
year = "2021",
doi = "10.1073/pnas.2108079118",
language = "English",
volume = "118",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
publisher = "The National Academy of Sciences of the United States of America",
number = "31",

}

RIS

TY - JOUR

T1 - GHB analogs confer neuroprotection through specific interaction with the CaMKIIα hub domain

AU - Leurs, Ulrike

AU - Klein, Anders B.

AU - McSpadden, Ethan D

AU - Griem-Krey, Nane

AU - Solbak, Sara M Ø

AU - Houlton, Josh

AU - Villumsen, Inge S

AU - Vogensen, Stine B

AU - Hamborg, Louise

AU - Gauger, Stine J

AU - Palmelund, Line B

AU - Larsen, Anne Sofie G.

AU - Shehata, Mohamed A

AU - Kelstrup, Christian D

AU - Olsen, Jesper V

AU - Bach, Anders

AU - Burnie, Robert O

AU - Kerr, D Steven

AU - Gowing, Emma K

AU - Teurlings, Selina M W

AU - Chi, Chris C

AU - Gee, Christine L

AU - Frølund, Bente

AU - Kornum, Birgitte R

AU - van Woerden, Geeske M

AU - Clausen, Rasmus P

AU - Kuriyan, John

AU - Clarkson, Andrew N

AU - Wellendorph, Petrine

N1 - Copyright © 2021 the Author(s). Published by PNAS.

PY - 2021

Y1 - 2021

N2 - 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.

AB - 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.

U2 - 10.1073/pnas.2108079118

DO - 10.1073/pnas.2108079118

M3 - Journal article

C2 - 34330837

VL - 118

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 31

M1 - e2108079118

ER -

ID: 275727076