Inactivation-mimicking block of the epithelial calcium channel TRPV6.
Journal
Science advances
ISSN: 2375-2548
Titre abrégé: Sci Adv
Pays: United States
ID NLM: 101653440
Informations de publication
Date de publication:
11 2020
11 2020
Historique:
received:
03
08
2020
accepted:
14
10
2020
entrez:
28
11
2020
pubmed:
29
11
2020
medline:
12
4
2022
Statut:
epublish
Résumé
Epithelial calcium channel TRPV6 plays vital roles in calcium homeostasis, and its dysregulation is implicated in multifactorial diseases, including cancers. Here, we study the molecular mechanism of selective nanomolar-affinity TRPV6 inhibition by (4-phenylcyclohexyl)piperazine derivatives (PCHPDs). We use x-ray crystallography and cryo-electron microscopy to solve the inhibitor-bound structures of TRPV6 and identify two types of inhibitor binding sites in the transmembrane region: (i) modulatory sites between the S1-S4 and pore domains normally occupied by lipids and (ii) the main site in the ion channel pore. Our structural data combined with mutagenesis, functional and computational approaches suggest that PCHPDs plug the open pore of TRPV6 and convert the channel into a nonconducting state, mimicking the action of calmodulin, which causes inactivation of TRPV6 channels under physiological conditions. This mechanism of inhibition explains the high selectivity and potency of PCHPDs and opens up unexplored avenues for the design of future-generation biomimetic drugs.
Identifiants
pubmed: 33246965
pii: 6/48/eabe1508
doi: 10.1126/sciadv.abe1508
pmc: PMC7695471
pii:
doi:
Substances chimiques
Calcium Channels
0
Calmodulin
0
TRPV Cation Channels
0
TRPV6 protein, human
0
Calcium
SY7Q814VUP
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NIGMS NIH HHS
ID : P41 GM103310
Pays : United States
Organisme : NCRR NIH HHS
ID : P41 RR001209
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS107253
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS083660
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA206573
Pays : United States
Informations de copyright
Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).
Références
J Mol Graph. 1996 Dec;14(6):354-60, 376
pubmed: 9195488
Nature. 2016 May 18;534(7607):347-51
pubmed: 27281200
J Cancer. 2020 Jan 1;11(2):374-387
pubmed: 31897233
Science. 2019 Sep 27;365(6460):1434-1440
pubmed: 31488702
Mol Cancer Ther. 2008 Feb;7(2):271-9
pubmed: 18245667
Cell Calcium. 2006 Feb;39(2):163-73
pubmed: 16356545
Sci Rep. 2017 Apr 04;7:45489
pubmed: 28374795
Nature. 2016 Jun 13;534(7608):506-11
pubmed: 27296226
J Comput Chem. 2005 Dec;26(16):1701-18
pubmed: 16211538
Am J Med Genet A. 2018 Sep;176(9):1950-1955
pubmed: 30144375
Cell Calcium. 2013 Apr;53(4):241-55
pubmed: 23357407
Nature. 2013 Dec 5;504(7478):113-8
pubmed: 24305161
Am J Hum Genet. 2018 Jun 7;102(6):1104-1114
pubmed: 29861107
Nat Struct Mol Biol. 2018 Jan;25(1):53-60
pubmed: 29323279
Angew Chem Int Ed Engl. 2015 Dec 1;54(49):14748-52
pubmed: 26457814
J Mol Graph. 1996 Feb;14(1):33-8, 27-8
pubmed: 8744570
Cancer Res. 2000 Feb 15;60(4):1002-8
pubmed: 10706116
J Comput Chem. 2004 Oct;25(13):1605-12
pubmed: 15264254
Bioorg Med Chem. 2013 Jun 1;21(11):3202-13
pubmed: 23602525
J Struct Biol. 2016 Jan;193(1):1-12
pubmed: 26592709
Nat Methods. 2017 Mar;14(3):290-296
pubmed: 28165473
Nat Commun. 2018 Jun 25;9(1):2465
pubmed: 29941865
Science. 2014 Dec 12;346(6215):1377-80
pubmed: 25504723
Phys Rev A Gen Phys. 1985 Mar;31(3):1695-1697
pubmed: 9895674
J Biol Chem. 2013 Feb 22;288(8):5278-90
pubmed: 23300090
Nat Commun. 2018 Oct 10;9(1):4198
pubmed: 30305626
J Bone Miner Res. 2007 Feb;22(2):274-85
pubmed: 17129178
Sci Rep. 2017 Sep 6;7(1):10669
pubmed: 28878326
Biophys J. 1997 May;72(5):2002-13
pubmed: 9129804
Pharmacol Rev. 2014 Jul;66(3):676-814
pubmed: 24951385
Elife. 2020 Aug 17;9:
pubmed: 32804077
Bone. 2010 Aug;47(2):301-8
pubmed: 20399919
Acta Crystallogr D Biol Crystallogr. 2010 Apr;66(Pt 4):486-501
pubmed: 20383002
J Bone Miner Res. 2008 Aug;23(8):1249-56
pubmed: 18348695
J Physiol. 2020 Feb 19;:
pubmed: 32073143
J Physiol. 2006 Nov 15;577(Pt 1):31-44
pubmed: 16959851
Proc Natl Acad Sci U S A. 2019 Apr 30;116(18):8869-8878
pubmed: 30975749
Sci Adv. 2018 Aug 15;4(8):eaau6088
pubmed: 30116787
Acta Crystallogr D Biol Crystallogr. 2012 Apr;68(Pt 4):352-67
pubmed: 22505256
Pharm Res. 2011 Feb;28(2):322-30
pubmed: 21057859
Nat Struct Mol Biol. 2018 Sep;25(9):805-813
pubmed: 30127359
Oncogene. 2007 Nov 15;26(52):7380-5
pubmed: 17533368
Nature. 2003 Dec 4;426(6966):517-24
pubmed: 14654832
Acta Crystallogr D Biol Crystallogr. 2010 Feb;66(Pt 2):125-32
pubmed: 20124692
J Struct Biol. 2005 Jul;151(1):41-60
pubmed: 15890530
PLoS One. 2013;8(3):e58866
pubmed: 23554944
Nat Methods. 2017 Apr;14(4):331-332
pubmed: 28250466
Cell Calcium. 2012 Dec;52(6):468-80
pubmed: 23040501
Nat Struct Mol Biol. 2019 Nov;26(11):994-998
pubmed: 31636415
Elife. 2019 Sep 30;8:
pubmed: 31566564
J Appl Crystallogr. 2007 Aug 1;40(Pt 4):658-674
pubmed: 19461840
J Chem Inf Model. 2018 Nov 26;58(11):2193-2202
pubmed: 30336018
Methods. 2007 Apr;41(4):475-88
pubmed: 17367719
J Chem Phys. 2007 Jan 7;126(1):014101
pubmed: 17212484
Nat Protoc. 2014 Nov;9(11):2574-85
pubmed: 25299155
Nature. 2018 Jan 11;553(7687):233-237
pubmed: 29258289
Cell Physiol Biochem. 2011;28(5):813-22
pubmed: 22178934
ACS Med Chem Lett. 2019 Aug 02;10(9):1341-1345
pubmed: 31531207
J Struct Biol. 2012 Dec;180(3):519-30
pubmed: 23000701