{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T19:22:48Z","timestamp":1789154568109,"version":"build-2803163510"},"reference-count":56,"publisher":"Elsevier BV","issue":"15","license":[{"start":{"date-parts":[[2017,4,1]],"date-time":"2017-04-01T00:00:00Z","timestamp":1491004800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"},{"start":{"date-parts":[[2020,9,3]],"date-time":"2020-09-03T00:00:00Z","timestamp":1599091200000},"content-version":"vor","delay-in-days":1251,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["MOP-68897"],"award-info":[{"award-number":["MOP-68897"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000038","name":"Natural Sciences and Engineering Research Council of Canada","doi-asserted-by":"publisher","award":["RGPIN-2014-04514"],"award-info":[{"award-number":["RGPIN-2014-04514"]}],"id":[{"id":"10.13039\/501100000038","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["jbc.org","elsevier.com","sciencedirect.com"],"crossmark-restriction":true},"short-container-title":["Journal of Biological Chemistry"],"published-print":{"date-parts":[[2017,4]]},"DOI":"10.1074\/jbc.m116.773697","type":"journal-article","created":{"date-parts":[[2017,2,8]],"date-time":"2017-02-08T01:25:18Z","timestamp":1486517118000},"page":"6414-6428","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":22,"title":["Free energy landscape remodeling of the cardiac pacemaker channel explains the molecular basis of familial sinus bradycardia"],"prefix":"10.1016","volume":"292","author":[{"given":"Stephen","family":"Boulton","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Madoka","family":"Akimoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sam","family":"Akbarizadeh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Melacini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"78","reference":[{"key":"10.1074\/jbc.M116.773697_bib1","doi-asserted-by":"crossref","first-page":"304","DOI":"10.1212\/WNL.0b013e31827dec42","article-title":"HCN channels: function and clinical implications","volume":"80","author":"Benarroch","year":"2013","journal-title":"Neurology"},{"key":"10.1074\/jbc.M116.773697_bib2","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1146\/annurev.physiol.68.040104.134728","article-title":"CNG and HCN channels: two peas, one pod","volume":"68","author":"Craven","year":"2006","journal-title":"Annu. Rev. Physiol"},{"key":"10.1074\/jbc.M116.773697_bib3","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1073\/pnas.1012750108","article-title":"Cytoplasmic cAMP-sensing domain of hyperpolarization-activated cation (HCN) channels uses two structurally distinct mechanisms to regulate voltage gating","volume":"108","author":"Wicks","year":"2011","journal-title":"Proc. Natl. Acad. Sci. U.S.A"},{"key":"10.1074\/jbc.M116.773697_bib4","doi-asserted-by":"crossref","first-page":"805","DOI":"10.1038\/35081088","article-title":"Molecular mechanism of cAMP modulation of HCN pacemaker channels","volume":"411","author":"Wainger","year":"2001","journal-title":"Nature"},{"key":"10.1074\/jbc.M116.773697_bib5","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1038\/nature01922","article-title":"Structural basis for modulation and agonist specificity of HCN pacemaker channels","volume":"425","author":"Zagotta","year":"2003","journal-title":"Nature"},{"key":"10.1074\/jbc.M116.773697_bib6","doi-asserted-by":"crossref","first-page":"1629","DOI":"10.1016\/j.str.2016.06.024","article-title":"Cyclic purine and pyrimidine nucleotides bind to the HCN2 ion channel and variably promote C-terminal domain interactions and opening","volume":"24","author":"Ng","year":"2016","journal-title":"Structure"},{"key":"10.1074\/jbc.M116.773697_bib7","doi-asserted-by":"crossref","first-page":"44811","DOI":"10.1074\/jbc.M111.297606","article-title":"Tetramerization dynamics of C-terminal domain underlies isoform-specific cAMP gating in hyperpolarization-activated cyclic nucleotide-gated channels","volume":"286","author":"Lolicato","year":"2011","journal-title":"J. Biol. Chem"},{"key":"10.1074\/jbc.M116.773697_bib8","doi-asserted-by":"crossref","first-page":"37082","DOI":"10.1074\/jbc.M110.152033","article-title":"Structural basis for the cAMP-dependent gating in the human HCN4 channel","volume":"285","author":"Xu","year":"2010","journal-title":"J. Biol. Chem"},{"key":"10.1074\/jbc.M116.773697_bib9","doi-asserted-by":"crossref","first-page":"22205","DOI":"10.1074\/jbc.M114.572164","article-title":"A mechanism for the auto-inhibition of hyperpolarization-activated cyclic nucleotide-gated (HCN) channel opening and its relief by cAMP","volume":"289","author":"Akimoto","year":"2014","journal-title":"J. Biol. Chem"},{"key":"10.1074\/jbc.M116.773697_bib10","doi-asserted-by":"crossref","first-page":"1627","DOI":"10.1016\/j.str.2016.09.002","article-title":"Distinct signaling roles of cIMP, cCMP, and cUMP","volume":"24","author":"Seifert","year":"2016","journal-title":"Structure"},{"key":"10.1074\/jbc.M116.773697_bib11","doi-asserted-by":"crossref","first-page":"542","DOI":"10.1161\/CIRCEP.110.949768","article-title":"cAMP sensitivity of HCN pacemaker channels determines basal heart rate but is not critical for autonomic rate control","volume":"3","author":"Schweizer","year":"2010","journal-title":"Circ. Arrhythm. Electrophysiol"},{"key":"10.1074\/jbc.M116.773697_bib12","doi-asserted-by":"crossref","first-page":"532","DOI":"10.1038\/nmeth.1341","article-title":"Mapping the structure and conformational movements of proteins with transition metal ion FRET","volume":"6","author":"Taraska","year":"2009","journal-title":"Nat. Methods"},{"key":"10.1074\/jbc.M116.773697_bib13","doi-asserted-by":"crossref","first-page":"17642","DOI":"10.1074\/jbc.M115.651877","article-title":"Role of dynamics in the autoinhibition and activation of the hyperpolarization-activated cyclic nucleotide-modulated (HCN) ion channels","volume":"290","author":"VanSchouwen","year":"2015","journal-title":"J. Biol. Chem"},{"key":"10.1074\/jbc.M116.773697_bib14","doi-asserted-by":"crossref","first-page":"655","DOI":"10.1016\/j.str.2007.04.012","article-title":"Gating of HCN channels by cyclic nucleotides: residue contacts that underlie ligand binding, selectivity, and efficacy","volume":"15","author":"Zhou","year":"2007","journal-title":"Structure"},{"key":"10.1074\/jbc.M116.773697_bib15","doi-asserted-by":"crossref","first-page":"384","DOI":"10.1093\/europace\/eut348","article-title":"Pacemaker activity of the human sinoatrial node: effects of HCN4 mutations on the hyperpolarization-activated current","volume":"16","author":"Verkerk","year":"2014","journal-title":"Europace"},{"key":"10.1074\/jbc.M116.773697_bib16","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1093\/eurheartj\/ehv582","article-title":"A gain-of-function mutation in the cardiac pacemaker HCN4 channel increasing cAMP sensitivity is associated with familial inappropriate sinus tachycardia","volume":"38","author":"Baruscotti","year":"2017","journal-title":"Eur. Heart J"},{"key":"10.1074\/jbc.M116.773697_bib17","doi-asserted-by":"crossref","first-page":"4117","DOI":"10.1113\/jphysiol.2013.253765","article-title":"Funny channel gene mutations associated with arrhythmias","volume":"591","author":"DiFrancesco","year":"2013","journal-title":"J. Physiol"},{"key":"10.1074\/jbc.M116.773697_bib18","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1056\/NEJMoa052475","article-title":"Familial sinus bradycardia associated with a mutation in the cardiac pacemaker channel","volume":"354","author":"Milanesi","year":"2006","journal-title":"N. Engl. J. Med"},{"key":"10.1074\/jbc.M116.773697_bib19","doi-asserted-by":"crossref","first-page":"1537","DOI":"10.1172\/JCI200316387","article-title":"Pacemaker channel dysfunction in a patient with sinus node disease","volume":"111","author":"Schulze-Bahr","year":"2003","journal-title":"J. Clin. Invest"},{"key":"10.1074\/jbc.M116.773697_bib20","doi-asserted-by":"crossref","first-page":"2116","DOI":"10.1016\/j.str.2012.09.017","article-title":"Local and global interpretations of a disease-causing mutation near the ligand entry path in hyperpolarization-activated cAMP-gated channel","volume":"20","author":"Xu","year":"2012","journal-title":"Structure"},{"key":"10.1074\/jbc.M116.773697_bib21","doi-asserted-by":"crossref","first-page":"28631","DOI":"10.1074\/jbc.M115.685305","article-title":"Mechanism of cAMP partial agonism in protein kinase G (PKG)","volume":"290","author":"VanSchouwen","year":"2015","journal-title":"J. Biol. Chem"},{"key":"10.1074\/jbc.M116.773697_bib22","doi-asserted-by":"crossref","first-page":"14231","DOI":"10.1073\/pnas.1312644110","article-title":"Signaling through dynamic linkers as revealed by PKA","volume":"110","author":"Akimoto","year":"2013","journal-title":"Proc. Nat. Acad. Sci. U.S.A"},{"key":"10.1074\/jbc.M116.773697_bib23","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1042\/BST20130282","article-title":"Tapping the translation potential of cAMP signalling: molecular basis for selectivity in cAMP agonism and antagonism as revealed by NMR","volume":"42","author":"Boulton","year":"2014","journal-title":"Biochem. Soc. Trans"},{"key":"10.1074\/jbc.M116.773697_bib24","doi-asserted-by":"crossref","first-page":"23682","DOI":"10.1074\/jbc.M109.011700","article-title":"Dynamically driven ligand selectivity in cyclic nucleotide binding domains","volume":"284","author":"Das","year":"2009","journal-title":"J. Biol. Chem"},{"key":"10.1074\/jbc.M116.773697_bib25","doi-asserted-by":"crossref","first-page":"19691","DOI":"10.1074\/jbc.M802164200","article-title":"Entropy-driven cAMP-dependent allosteric control of inhibitory interactions in exchange proteins directly activated by cAMP","volume":"283","author":"Das","year":"2008","journal-title":"J. Biol. Chem"},{"key":"10.1074\/jbc.M116.773697_bib26","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1074\/jbc.M607706200","article-title":"A model for agonism and antagonism in an ancient and ubiquitous cAMP-binding domain","volume":"282","author":"Das","year":"2007","journal-title":"J. Biol. Chem"},{"key":"10.1074\/jbc.M116.773697_bib27","doi-asserted-by":"crossref","first-page":"6133","DOI":"10.1073\/pnas.1017311108","article-title":"Mapping allostery through the covariance analysis of NMR chemical shifts","volume":"108","author":"Selvaratnam","year":"2011","journal-title":"Proc. Nat. Acad. Sci. U.S.A"},{"key":"10.1074\/jbc.M116.773697_bib28","doi-asserted-by":"crossref","first-page":"e48707","DOI":"10.1371\/journal.pone.0048707","article-title":"The auto-inhibitory role of the EPAC hinge helix as mapped by NMR","volume":"7","author":"Selvaratnam","year":"2012","journal-title":"PLoS One"},{"key":"10.1074\/jbc.M116.773697_bib29","doi-asserted-by":"crossref","first-page":"630","DOI":"10.1016\/j.bpj.2011.12.030","article-title":"The projection analysis of NMR chemical shifts reveals extended EPAC autoinhibition determinants","volume":"102","author":"Selvaratnam","year":"2012","journal-title":"Biophys. J"},{"key":"10.1074\/jbc.M116.773697_bib30","doi-asserted-by":"crossref","first-page":"6267","DOI":"10.1021\/acs.chemrev.5b00718","article-title":"Advances in NMR methods to map allosteric sites: from models to translation","volume":"116","author":"Boulton","year":"2016","journal-title":"Chem. Rev"},{"key":"10.1074\/jbc.M116.773697_bib31","doi-asserted-by":"crossref","first-page":"6263","DOI":"10.1021\/acs.chemrev.6b00283","article-title":"Introduction to protein ensembles and allostery","volume":"116","author":"Nussinov","year":"2016","journal-title":"Chem. Rev"},{"key":"10.1074\/jbc.M116.773697_bib32","doi-asserted-by":"crossref","first-page":"890","DOI":"10.1038\/nchembio.2212","article-title":"Protein dynamics: conformational footprints","volume":"12","author":"Ma","year":"2016","journal-title":"Nat. Chem. Biol"},{"key":"10.1074\/jbc.M116.773697_bib33","doi-asserted-by":"crossref","first-page":"6503","DOI":"10.1021\/acs.chemrev.5b00590","article-title":"Protein allostery and conformational dynamics","volume":"116","author":"Guo","year":"2016","journal-title":"Chem. Rev"},{"key":"10.1074\/jbc.M116.773697_bib34","doi-asserted-by":"crossref","first-page":"E6776","DOI":"10.1073\/pnas.1610142113","article-title":"Unidirectional allostery in the regulatory subunit RI\u03b1 facilitates efficient deactivation of protein kinase A","volume":"113","author":"Guo","year":"2016","journal-title":"Proc. Nat. Acad. Sci. U.S.A"},{"key":"10.1074\/jbc.M116.773697_bib35","doi-asserted-by":"crossref","first-page":"2771","DOI":"10.1016\/j.bpj.2015.04.035","article-title":"Dynamically driven protein allostery exhibits disparate responses for fast and slow motions","volume":"108","author":"Guo","year":"2015","journal-title":"Biophys. J"},{"key":"10.1074\/jbc.M116.773697_bib36","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1007\/s10858-011-9538-9","article-title":"Complete determination of the Pin1 catalytic domain thermodynamic cycle by NMR lineshape analysis","volume":"51","author":"Greenwood","year":"2011","journal-title":"J. Biomol. NMR"},{"key":"10.1074\/jbc.M116.773697_bib37","doi-asserted-by":"crossref","first-page":"6508","DOI":"10.1039\/C4CP00110A","article-title":"NMR mapping of protein conformational landscapes using coordinated behavior of chemical shifts upon ligand binding","volume":"16","author":"Cembran","year":"2014","journal-title":"Phys. Chem. Chem. Phys"},{"key":"10.1074\/jbc.M116.773697_bib38","doi-asserted-by":"crossref","first-page":"1739","DOI":"10.1016\/j.bbapap.2016.08.017","article-title":"NMR structure and conformational dynamics of AtPDFL2.1, a defensin-like peptide from Arabidopsis thaliana","volume":"1864","author":"Omidvar","year":"2016","journal-title":"Biochim. Biophys. Acta"},{"key":"10.1074\/jbc.M116.773697_bib39","doi-asserted-by":"crossref","first-page":"942","DOI":"10.1016\/j.bbapap.2010.10.012","article-title":"An introduction to NMR-based approaches for measuring protein dynamics","volume":"1814","author":"Kleckner","year":"2011","journal-title":"Biochim. Biophys. Acta"},{"key":"10.1074\/jbc.M116.773697_bib40","doi-asserted-by":"crossref","first-page":"10777","DOI":"10.1021\/jacs.5b06557","article-title":"Measurement of state-specific association constants in allosteric sensors through molecular stapling and NMR","volume":"137","author":"Moleschi","year":"2015","journal-title":"J. Am. Chem. Soc"},{"key":"10.1074\/jbc.M116.773697_bib41","doi-asserted-by":"crossref","first-page":"7306","DOI":"10.1038\/srep07306","article-title":"A tool set to map allosteric networks through the NMR chemical shift covariance analysis","volume":"4","author":"Boulton","year":"2014","journal-title":"Sci. Rep"},{"key":"10.1074\/jbc.M116.773697_bib42","doi-asserted-by":"crossref","first-page":"727","DOI":"10.1007\/BF00404280","article-title":"A heteronuclear correlation experiment for simultaneous determination of 15N longitudinal decay and chemical exchange rates of systems in slow equilibrium","volume":"4","author":"Farrow","year":"1994","journal-title":"J. Biomol. NMR"},{"key":"10.1074\/jbc.M116.773697_bib43","doi-asserted-by":"crossref","first-page":"959","DOI":"10.1016\/S0896-6273(03)00753-0","article-title":"Regulation of hyperpolarization-activated HCN channels by cAMP through a gating switch in binding domain symmetry","volume":"40","author":"Ulens","year":"2003","journal-title":"Neuron"},{"key":"10.1074\/jbc.M116.773697_bib44","doi-asserted-by":"crossref","first-page":"10936","DOI":"10.1021\/acs.jpcb.6b07735","article-title":"Structural basis of tonic inhibition by dimers of dimers in hyperpolarization-activated cyclic-nucleotide-modulated (HCN) ion channels","volume":"120","author":"VanSchouwen","year":"2016","journal-title":"J. Phys. Chem"},{"key":"10.1074\/jbc.M116.773697_bib45","doi-asserted-by":"crossref","first-page":"e20143","DOI":"10.7554\/eLife.20143","article-title":"A dynamic molecular basis for malfunction in disease mutants of p97\/VCP","volume":"5","author":"Schuetz","year":"2016","journal-title":"eLife"},{"key":"10.1074\/jbc.M116.773697_bib46","doi-asserted-by":"crossref","first-page":"E6939","DOI":"10.1073\/pnas.1611418113","article-title":"Probing the free energy landscapes of ALS disease mutants of SOD1 by NMR spectroscopy","volume":"116","author":"Sekhar","year":"2016","journal-title":"Proc. Natl. Acad. Sci. U.S.A"},{"key":"10.1074\/jbc.M116.773697_bib47","doi-asserted-by":"crossref","first-page":"3716","DOI":"10.1073\/pnas.1502299112","article-title":"Dysfunctional conformational dynamics of protein kinase A induced by a lethal mutant of phospholamban hinder phosphorylation","volume":"112","author":"Kim","year":"2015","journal-title":"Proc. Natl. Acad. Sci. U.S.A"},{"key":"10.1074\/jbc.M116.773697_bib48","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1016\/j.cell.2013.03.034","article-title":"Allostery in disease and in drug discovery","volume":"153","author":"Nussinov","year":"2013","journal-title":"Cell"},{"key":"10.1074\/jbc.M116.773697_bib49","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1007\/BF00197809","article-title":"NMRPipe: a multidimensional spectral processing system based on UNIX pipes","volume":"6","author":"Delaglio","year":"1995","journal-title":"J. Biomol. NMR"},{"key":"10.1074\/jbc.M116.773697_bib50","series-title":"Sparky3","author":"Goddard","year":"2008"},{"key":"10.1074\/jbc.M116.773697_bib51","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1007\/s10858-009-9333-z","article-title":"TALOS+: a hybrid method for predicting protein backbone torsion angles from NMR chemical shifts","volume":"44","author":"Shen","year":"2009","journal-title":"J. Biomol. NMR"},{"key":"10.1074\/jbc.M116.773697_bib52","doi-asserted-by":"crossref","first-page":"12547","DOI":"10.1021\/bi9913707","article-title":"Backbone dynamics of inactive, active, and effector-bound Cdc42Hs from measurements of 15N relaxation parameters at multiple field strengths","volume":"38","author":"Loh","year":"1999","journal-title":"Biochemistry"},{"key":"10.1074\/jbc.M116.773697_bib53","doi-asserted-by":"crossref","first-page":"873","DOI":"10.1006\/jmbi.2001.5083","article-title":"The role of backbone motions in ligand binding to the c-Src SH3 domain","volume":"313","author":"Wang","year":"2001","journal-title":"J. Mol. Biol"},{"key":"10.1074\/jbc.M116.773697_bib54","doi-asserted-by":"crossref","first-page":"2133","DOI":"10.1006\/jmbi.1998.2429","article-title":"Temperature dependence of intramolecular dynamics of the basic leucine zipper of GCN4: implications for the entropy of association with DNA","volume":"285","author":"Bracken","year":"1999","journal-title":"J. Mol. Biol"},{"key":"10.1074\/jbc.M116.773697_bib55","doi-asserted-by":"crossref","first-page":"831","DOI":"10.1038\/nsmb1132","article-title":"Dynamically driven protein allostery","volume":"13","author":"Popovych","year":"2006","journal-title":"Nat. Struct. Mol. Biol"},{"key":"10.1074\/jbc.M116.773697_bib56","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/0263-7855(96)00009-4","article-title":"MOLMOL: A program for display and analysis of macromolecular structures","volume":"14","author":"Koradi","year":"1996","journal-title":"J. Mol. Graph"}],"container-title":["Journal of Biological Chemistry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0021925820449737?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0021925820449737?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1074\/jbc.M116.773697","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,5,1]],"date-time":"2021-05-01T13:27:52Z","timestamp":1619875672000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S0021925820449737"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,4]]},"references-count":56,"journal-issue":{"issue":"15","published-print":{"date-parts":[[2017,4]]}},"alternative-id":["S0021925820449737"],"URL":"https:\/\/doi.org\/10.1074\/jbc.m116.773697","relation":{},"ISSN":["0021-9258"],"issn-type":[{"value":"0021-9258","type":"print"}],"subject":[],"published":{"date-parts":[[2017,4]]},"assertion":[{"value":"Elsevier","name":"publisher","label":"This article is maintained by"},{"value":"Free energy landscape remodeling of the cardiac pacemaker channel explains the molecular basis of familial sinus bradycardia","name":"articletitle","label":"Article Title"},{"value":"Journal of Biological Chemistry","name":"journaltitle","label":"Journal Title"},{"value":"https:\/\/doi.org\/10.1074\/jbc.M116.773697","name":"articlelink","label":"CrossRef DOI link to publisher maintained version"},{"value":"article","name":"content_type","label":"Content Type"},{"value":"\u00a9 2017 ASBMB. Currently published by Elsevier Inc; originally published by American Society for Biochemistry and Molecular Biology.","name":"copyright","label":"Copyright"}]}}