Structural basis of selective TRPM7 inhibition by the anticancer agent CCT128930

Nadezhdin, Kirill D.; Correia, Leonor; Shalygin, Alexey; Aktolun, Muhammed; Neuberger, Arthur; Gudermann, Thomas; Kurnikova, Maria G.; Chubanov, Vladimir; Sobolevsky, Alexander I.

doi:10.1016/j.celrep.2024.114108

Structural basis of selective TRPM7 inhibition by the anticancer agent CCT128930

Journal Article · Fri Apr 12 00:00:00 EDT 2024 · Cell Reports

DOI:https://doi.org/10.1016/j.celrep.2024.114108· OSTI ID:2471667

Nadezhdin, Kirill D. ^[1]; Correia, Leonor ^[2]; Shalygin, Alexey ^[3]; Aktolun, Muhammed ^[4]; Neuberger, Arthur ^[1]; Gudermann, Thomas ^[5]; Kurnikova, Maria G. ^[4]; Chubanov, Vladimir ^[2]; Sobolevsky, Alexander I. ^[1]

Columbia Univ., New York, NY (United States)
Ludwig Maximilian Univ. of Munich, Munich (Germany)
Comprehensive Pneumology Center, Munich (Germany)
Carnegie Mellon Univ., Pittsburgh, PA (United States)
Ludwig Maximilian Univ. of Munich, Munich (Germany); Comprehensive Pneumology Center, Munich (Germany)

TRP channels are implicated in various diseases, but high structural similarity between them makes selective pharmacological modulation challenging. Here, we study the molecular mechanism underlying specific inhibition of the TRPM7 channel, which is essential for cancer cell proliferation, by the anticancer agent CCT128930 (CCT). Using cryo-EM, functional analysis, and MD simulations, we show that CCT binds to a vanilloid-like (VL) site, stabilizing TRPM7 in the closed non-conducting state. Similar to other allosteric inhibitors of TRPM7, NS8593 and VER155008, binding of CCT is accompanied by displacement of a lipid that resides in the VL site in the apo condition. Moreover, we demonstrate the principal role of several residues in the VL site enabling CCT to inhibit TRPM7 without impacting the homologous TRPM6 channel. Hence, our results uncover the central role of the VL site for the selective interaction of TRPM7 with small molecules that can be explored in future drug design.

View Accepted Manuscript (DOE)

Research Organization:: Pacific Northwest National Laboratory (PNNL), Richland, WA (United States). Environmental Molecular Sciences Laboratory (EMSL)

Sponsoring Organization:: USDOE Office of Science (SC), Biological and Environmental Research (BER)

Grant/Contract Number:: AC05-76RL01830

OSTI ID:: 2471667

Journal Information:: Cell Reports, Journal Name: Cell Reports Journal Issue: 4 Vol. 43; ISSN 2211-1247

Publisher:: ElsevierCopyright Statement

Country of Publication:: United States

Language:: English

References (58)

Development and testing of a general amber force field Wang, Junmei; Wolf, Romain M.; Caldwell, James W. Journal of Computational Chemistry, Vol. 25, Issue 9 https://doi.org/10.1002/jcc.20035	journal	January 2004
UCSF Chimera?A visualization system for exploratory research and analysis Pettersen, Eric F.; Goddard, Thomas D.; Huang, Conrad C. Journal of Computational Chemistry, Vol. 25, Issue 13 https://doi.org/10.1002/jcc.20084	journal	January 2004
The Amber biomolecular simulation programs Case, David A.; Cheatham, Thomas E.; Darden, Tom Journal of Computational Chemistry, Vol. 26, Issue 16 https://doi.org/10.1002/jcc.20290	journal	January 2005
CHARMM-GUI: A web-based graphical user interface for CHARMM Jo, Sunhwan; Kim, Taehoon; Iyer, Vidyashankara G. Journal of Computational Chemistry, Vol. 29, Issue 11 https://doi.org/10.1002/jcc.20945	journal	March 2008
CHARMM-GUI Membrane Builder toward realistic biological membrane simulations Wu, Emilia L.; Cheng, Xi; Jo, Sunhwan Journal of Computational Chemistry, Vol. 35, Issue 27 https://doi.org/10.1002/jcc.23702	journal	August 2014
Suppression of TRPM7 enhances TRAIL‐induced apoptosis in triple‐negative breast cancer cells Song, Chiman; Choi, Seunghye; Oh, Ki‐Bong Journal of Cellular Physiology, Vol. 235, Issue 12 https://doi.org/10.1002/jcp.29820	journal	May 2020
UCSF ChimeraX : Structure visualization for researchers, educators, and developers Pettersen, Eric F.; Goddard, Thomas D.; Huang, Conrad C. Protein Science, Vol. 30, Issue 1 https://doi.org/10.1002/pro.3943	journal	October 2020
Structural mechanism of TRPM7 channel regulation by intracellular magnesium Schmidt, Eva; Narangoda, Chamali; Nörenberg, Wolfgang Cellular and Molecular Life Sciences, Vol. 79, Issue 5 https://doi.org/10.1007/s00018-022-04192-7	journal	April 2022
Activation of TRPM7 channels by small molecules under physiological conditions Hofmann, T.; Schäfer, S.; Linseisen, M. Pflügers Archiv - European Journal of Physiology, Vol. 466, Issue 12 https://doi.org/10.1007/s00424-014-1488-0	journal	March 2014
Numerical integration of the cartesian equations of motion of a system with constraints: molecular dynamics of n-alkanes Ryckaert, Jean-Paul; Ciccotti, Giovanni; Berendsen, Herman J. C. Journal of Computational Physics, Vol. 23, Issue 3 https://doi.org/10.1016/0021-9991(77)90098-5	journal	March 1977
VMD: Visual molecular dynamics Humphrey, William; Dalke, Andrew; Schulten, Klaus Journal of Molecular Graphics, Vol. 14, Issue 1 https://doi.org/10.1016/0263-7855(96)00018-5	journal	February 1996
Regulation of Vertebrate Cellular Mg2+ Homeostasis by TRPM7 Schmitz, Carsten; Perraud, Anne-Laure; Johnson, Catherine O. Cell, Vol. 114, Issue 2 https://doi.org/10.1016/S0092-8674(03)00556-7	journal	July 2003
HOLE: A program for the analysis of the pore dimensions of ion channel structural models Smart, Oliver S.; Neduvelil, Joseph G.; Wang, Xiaonan Journal of Molecular Graphics, Vol. 14, Issue 6 https://doi.org/10.1016/S0263-7855(97)00009-X	journal	December 1996
CCT128930 is a novel and potent antagonist of TRPM7 channel Guan, Ziyue; Chen, Xueqin; Fang, Sui Biochemical and Biophysical Research Communications, Vol. 560 https://doi.org/10.1016/j.bbrc.2021.04.119	journal	June 2021
Role of TRPM7 kinase in cancer Meng, Selena; Alanazi, Rahmah; Ji, Delphine Cell Calcium, Vol. 96 https://doi.org/10.1016/j.ceca.2021.102400	journal	June 2021
Modulators of TRPM7 and its potential as a drug target for brain tumours Ji, Delphine; Fleig, Andrea; Horgen, F. David Cell Calcium, Vol. 101 https://doi.org/10.1016/j.ceca.2021.102521	journal	January 2022
Pharmacological agents selectively acting on the channel moieties of TRPM6 and TRPM7 Rössig, Anna; Hill, Kerstin; Nörenberg, Wolfgang Cell Calcium, Vol. 106 https://doi.org/10.1016/j.ceca.2022.102640	journal	September 2022
The TRPM7 Chanzyme Is Cleaved to Release a Chromatin-Modifying Kinase Krapivinsky, Grigory; Krapivinsky, Luba; Manasian, Yunona Cell, Vol. 157, Issue 5 https://doi.org/10.1016/j.cell.2014.03.046	journal	May 2014
RELION: Implementation of a Bayesian approach to cryo-EM structure determination Scheres, Sjors H. W. Journal of Structural Biology, Vol. 180, Issue 3, p. 519-530 https://doi.org/10.1016/j.jsb.2012.09.006	journal	December 2012
A Non-covalent Ligand Reveals Biased Agonism of the TRPA1 Ion Channel Liu, Chang; Reese, Rebecca; Vu, Simon Neuron, Vol. 109, Issue 2 https://doi.org/10.1016/j.neuron.2020.10.014	journal	January 2021
A pan-cancer-bioinformatic-based literature review of TRPM7 in cancers Liu, Hengrui; Dilger, James P.; Lin, Jun Pharmacology & Therapeutics, Vol. 240 https://doi.org/10.1016/j.pharmthera.2022.108302	journal	December 2022
LigPlot+: Multiple Ligand–Protein Interaction Diagrams for Drug Discovery Laskowski, Roman A.; Swindells, Mark B. Journal of Chemical Information and Modeling, Vol. 51, Issue 10 https://doi.org/10.1021/ci200227u	journal	October 2011
PTRAJ and CPPTRAJ: Software for Processing and Analysis of Molecular Dynamics Trajectory Data Roe, Daniel R.; Cheatham, Thomas E. Journal of Chemical Theory and Computation, Vol. 9, Issue 7 https://doi.org/10.1021/ct400341p	journal	June 2013
Lipid14: The Amber Lipid Force Field Dickson, Callum J.; Madej, Benjamin D.; Skjevik, Åge A. Journal of Chemical Theory and Computation, Vol. 10, Issue 2 https://doi.org/10.1021/ct4010307	journal	January 2014
LTRPC7 is a Mg·ATP-regulated divalent cation channel required for cell viability Nadler, Monica J. S.; Hermosura, Meredith C.; Inabe, Kazunori Nature, Vol. 411, Issue 6837 https://doi.org/10.1038/35079092	journal	May 2001
Identification of a cold receptor reveals a general role for TRP channels in thermosensation McKemy, David D.; Neuhausser, Werner M.; Julius, David Nature, Vol. 416, Issue 6876 https://doi.org/10.1038/nature719	journal	February 2002
The TRPM7 channel is inactivated by PIP2 hydrolysis Runnels, Loren W.; Yue, Lixia; Clapham, David E. Nature Cell Biology, Vol. 4, Issue 5 https://doi.org/10.1038/ncb781	journal	April 2002
cryoSPARC: algorithms for rapid unsupervised cryo-EM structure determination Punjani, Ali; Rubinstein, John L.; Fleet, David J. Nature Methods, Vol. 14, Issue 3 https://doi.org/10.1038/nmeth.4169	journal	February 2017
MotionCor2: anisotropic correction of beam-induced motion for improved cryo-electron microscopy Zheng, Shawn Q.; Palovcak, Eugene; Armache, Jean-Paul Nature Methods, Vol. 14, Issue 4 https://doi.org/10.1038/nmeth.4193	journal	February 2017
Induction of epithelial–mesenchymal transition (EMT) in breast cancer cells is calcium signal dependent Davis, F. M.; Azimi, I.; Faville, R. A. Oncogene, Vol. 33, Issue 18 https://doi.org/10.1038/onc.2013.187	journal	May 2013
Inhibition of TRPM7 blocks MRTF/SRF-dependent transcriptional and tumorigenic activity Voringer, Sandra; Schreyer, Laura; Nadolni, Wiebke Oncogene, Vol. 39, Issue 11 https://doi.org/10.1038/s41388-019-1140-8	journal	December 2019
Extracellular cap domain is an essential component of the TRPV1 gating mechanism Nadezhdin, Kirill D.; Neuberger, Arthur; Nikolaev, Yury A. Nature Communications, Vol. 12, Issue 1 https://doi.org/10.1038/s41467-021-22507-3	journal	April 2021
Human TRPV1 structure and inhibition by the analgesic SB-366791 Neuberger, Arthur; Oda, Mai; Nikolaev, Yury A. Nature Communications, Vol. 14, Issue 1 https://doi.org/10.1038/s41467-023-38162-9	journal	April 2023
Structural mechanisms of TRPM7 activation and inhibition Nadezhdin, Kirill D.; Correia, Leonor; Narangoda, Chamali Nature Communications, Vol. 14, Issue 1 https://doi.org/10.1038/s41467-023-38362-3	journal	May 2023
Advances in TRP channel drug discovery: from target validation to clinical studies Koivisto, Ari-Pekka; Belvisi, Maria G.; Gaudet, Rachelle Nature Reviews Drug Discovery, Vol. 21, Issue 1 https://doi.org/10.1038/s41573-021-00268-4	journal	September 2021
TRPM channels in health and disease Chubanov, Vladimir; Köttgen, Michael; Touyz, Rhian M. Nature Reviews Nephrology, Vol. 20, Issue 3 https://doi.org/10.1038/s41581-023-00777-y	journal	October 2023
Structures of the TRPM5 channel elucidate mechanisms of activation and inhibition Ruan, Zheng; Haley, Emery; Orozco, Ian J. Nature Structural & Molecular Biology, Vol. 28, Issue 7 https://doi.org/10.1038/s41594-021-00607-4	journal	June 2021
Structural mechanism of heat-induced opening of a temperature-sensitive TRP channel Nadezhdin, Kirill D.; Neuberger, Arthur; Trofimov, Yuri A. Nature Structural & Molecular Biology, Vol. 28, Issue 7 https://doi.org/10.1038/s41594-021-00615-4	journal	July 2021
TRPM6 and TRPM7 differentially contribute to the relief of heteromeric TRPM6/7 channels from inhibition by cytosolic Mg2+ and Mg·ATP Ferioli, Silvia; Zierler, Susanna; Zaißerer, Joanna Scientific Reports, Vol. 7, Issue 1 https://doi.org/10.1038/s41598-017-08144-1	journal	August 2017
TRPM7 contributes to progressive nephropathy Suzuki, Sayuri; Penner, Reinhold; Fleig, Andrea Scientific Reports, Vol. 10, Issue 1 https://doi.org/10.1038/s41598-020-59355-y	journal	February 2020
Disruption of TRPM6/TRPM7 complex formation by a mutation in the TRPM6 gene causes hypomagnesemia with secondary hypocalcemia Chubanov, Vladimir; Waldegger, Siegfried; Schnitzler, Michael Mederos y. Proceedings of the National Academy of Sciences, Vol. 101, Issue 9 https://doi.org/10.1073/pnas.0305252101	journal	February 2004
Activation of TRPM3 by a potent synthetic ligand reveals a role in peptide release Held, Katharina; Kichko, Tatjana; De Clercq, Katrien Proceedings of the National Academy of Sciences, Vol. 112, Issue 11 https://doi.org/10.1073/pnas.1419845112	journal	March 2015
TRPM7 senses oxidative stress to release Zn ²⁺ from unique intracellular vesicles Abiria, Sunday A.; Krapivinsky, Grigory; Sah, Rajan Proceedings of the National Academy of Sciences, Vol. 114, Issue 30 https://doi.org/10.1073/pnas.1707380114	journal	July 2017
TRPM7 is the central gatekeeper of intestinal mineral absorption essential for postnatal survival Mittermeier, Lorenz; Demirkhanyan, Lusine; Stadlbauer, Benjamin Proceedings of the National Academy of Sciences, Vol. 116, Issue 10 https://doi.org/10.1073/pnas.1810633116	journal	February 2019
Structure of the mammalian TRPM7, a magnesium channel required during embryonic development Duan, Jingjing; Li, Zongli; Li, Jian Proceedings of the National Academy of Sciences, Vol. 115, Issue 35 https://doi.org/10.1073/pnas.1810719115	journal	August 2018
Chimeric green fluorescent protein-aequorin as bioluminescent Ca ²⁺ reporters at the single-cell level Baubet, Valérie; Le Mouellic, Hervé; Campbell, Anthony K. Proceedings of the National Academy of Sciences, Vol. 97, Issue 13 https://doi.org/10.1073/pnas.97.13.7260	journal	June 2000
TRPM7 Provides an Ion Channel Mechanism for Cellular Entry of Trace Metal Ions Monteilh-Zoller, Mahealani K.; Hermosura, Meredith C.; Nadler, Monica J. S. The Journal of General Physiology, Vol. 121, Issue 1 https://doi.org/10.1085/jgp.20028740	journal	December 2002
Features and development of Coot Emsley, P.; Lohkamp, B.; Scott, W. G. Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 4 https://doi.org/10.1107/S0907444910007493	journal	March 2010
Towards automated crystallographic structure refinement with phenix.refine Afonine, Pavel V.; Grosse-Kunstleve, Ralf W.; Echols, Nathaniel Acta Crystallographica Section D Biological Crystallography, Vol. 68, Issue 4 https://doi.org/10.1107/S0907444912001308	journal	March 2012
Natural and synthetic modulators of SK (K_ca2) potassium channels inhibit magnesium‐dependent activity of the kinase‐coupled cation channel TRPM7 Chubanov, V.; Mederos y. Schnitzler, M.; Meißner, M. British Journal of Pharmacology, Vol. 166, Issue 4 https://doi.org/10.1111/j.1476-5381.2012.01855.x	journal	May 2012
Prostaglandin E2 increases migration and proliferation of human glioblastoma cells by activating transient receptor potential melastatin 7 channels Tian, Yafei; Yang, Tingting; Yu, Shuntai Journal of Cellular and Molecular Medicine, Vol. 22, Issue 12 https://doi.org/10.1111/jcmm.13931	journal	October 2018
TRP-PLIK, a Bifunctional Protein with Kinase and Ion Channel Activities Runnels, Loren W.; Yue, Lixia; Clapham, David E. Science, Vol. 291, Issue 5506 https://doi.org/10.1126/science.1058519	journal	February 2001
Deletion of Trpm7 Disrupts Embryonic Development and Thymopoiesis Without Altering Mg ²⁺ Homeostasis Jin, Jie; Desai, Bimal N.; Navarro, Betsy Science, Vol. 322, Issue 5902 https://doi.org/10.1126/science.1163493	journal	October 2008
Ligand-Binding Sites in Vanilloid-Subtype TRP Channels Yelshanskaya, Maria V.; Sobolevsky, Alexander I. Frontiers in Pharmacology, Vol. 13 https://doi.org/10.3389/fphar.2022.900623	journal	May 2022
Mapping TRPM7 Function by NS8593 Chubanov, Vladimir; Gudermann, Thomas International Journal of Molecular Sciences, Vol. 21, Issue 19 https://doi.org/10.3390/ijms21197017	journal	September 2020
TRPM6 is Essential for Magnesium Uptake and Epithelial Cell Function in the Colon Luongo, Francesca; Pietropaolo, Giuseppe; Gautier, Mathieu Nutrients, Vol. 10, Issue 6 https://doi.org/10.3390/nu10060784	journal	June 2018
Accelerated cryo-EM structure determination with parallelisation using GPUs in RELION-2 Kimanius, Dari; Forsberg, Björn O.; Scheres, Sjors HW eLife, Vol. 5 https://doi.org/10.7554/eLife.18722	journal	November 2016
Epithelial magnesium transport by TRPM6 is essential for prenatal development and adult survival Chubanov, Vladimir; Ferioli, Silvia; Wisnowsky, Annika eLife, Vol. 5 https://doi.org/10.7554/eLife.20914	journal	December 2016

Similar Records

Human TRPV1 structure and inhibition by the analgesic SB-366791

Journal Article · Fri Apr 28 00:00:00 EDT 2023 · Nature Communications · OSTI ID:2425440

TRPV3 activation by different agonists accompanied by lipid dissociation from the vanilloid site

Journal Article · Wed May 01 00:00:00 EDT 2024 · Science Advances · OSTI ID:2471644

Structural mechanisms of TRPV6 inhibition by ruthenium red and econazole

Journal Article · Mon Nov 01 00:00:00 EDT 2021 · Nature Communications · OSTI ID:1903932

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
CCT128930
Cell biology
Molecular biology
TRP channel
TRPM7
calcium
cancer
cryo-EM
drug
inhibitor
lipids
magnesium

Structural basis of selective TRPM7 inhibition by the anticancer agent CCT128930

Citation Formats

References (58)

Similar Records

Related Subjects