{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T14:52:54Z","timestamp":1786978374082,"version":"build-2736575974"},"reference-count":78,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2004,2,3]],"date-time":"2004-02-03T00:00:00Z","timestamp":1075766400000},"content-version":"vor","delay-in-days":4508,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Proteins"],"published-print":{"date-parts":[[1991,10]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Calcium sensitizers are drugs which increase force development in striated muscle by sensitizing myofilaments to Ca\n                    <jats:sup>2+<\/jats:sup>\n                    . This can happen by increasing Ca\n                    <jats:sup>2+<\/jats:sup>\n                    affinity of the regulatory domain of Ca\n                    <jats:sup>2+<\/jats:sup>\n                    binding protein troponin C. High resolution crystal structures of two calcium binding proteins, calmodulin (Babu et al.: J. Mol. Biol. 203:191\u2013204, 1988) and skeletal troponin C (Satyshur et al.: J. Biol. Chem. 263:1628\u20131647, 1988; Herzber et al.: J. Mol. Biol. 203:761\u2013779, 1988), have recently been published. This makes it possible to model in detail the calcium\u2010sensitizing action of drugs on troponin C.\n                  <\/jats:p>\n                  <jats:p>In this study a model of human cardiac troponin C in three\u2010calcium state has been constructed. When calcium is bound to calcium site II of cardiac troponin C an open conformation of the protein results, which has a hydrophobic pocket surrounded by a few polar side chains. Complexation of three drugs, trifluoperazine, bepridil, and pimobendan, to the hydrophobic pocket is studied using energy minimization techniques. Two different binding modes are found, which differ in the location of a strong electrostatic interaction. In analogy with the crystal structure of skeletal troponin C it is hypothezed that in cardiac troponin C an interaction occurs between Gln\u201050 and Asp\u201088, which has a long\u2010range effect on calcium binding. The binding modes of drugs, where a strong interaction with Asp\u201088 exists, can effectively prevent the interaction between Asp\u201088 and Gln\u201050 in the protein, and are proposed to be responsible for the calcium\u2010sensitizing properties of the studied drugs.<\/jats:p>","DOI":"10.1002\/prot.340110202","type":"journal-article","created":{"date-parts":[[2005,5,28]],"date-time":"2005-05-28T21:12:21Z","timestamp":1117314741000},"page":"79-94","source":"Crossref","is-referenced-by-count":25,"title":["A model for human cardiac troponin C and for modulation of its Ca\n                    <sup>2+<\/sup>\n                    affinity by drugs"],"prefix":"10.1002","volume":"11","author":[{"given":"Martti","family":"Ovaska","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jyrki","family":"Taskinen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2004,2,3]]},"reference":[{"key":"e_1_2_1_2_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.bi.58.070189.004511"},{"key":"e_1_2_1_3_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1432-1033.1980.tb04302.x"},{"key":"e_1_2_1_4_2","doi-asserted-by":"crossref","first-page":"12370","DOI":"10.1016\/S0021-9258(18)63868-2","article-title":"Site\u2010directed mutation of the trigger calcium\u2010binding sites in cardiac troponin C","volume":"264","author":"Putkey J. A.","year":"1989","journal-title":"J. Biol. Chem."},{"key":"e_1_2_1_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/0014-5793(88)80073-5"},{"key":"e_1_2_1_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/0014-5793(89)80420-X"},{"key":"e_1_2_1_7_2","doi-asserted-by":"publisher","DOI":"10.1021\/ar50150a004"},{"key":"e_1_2_1_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/0022-2836(86)90468-7"},{"key":"e_1_2_1_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/325826a0"},{"key":"e_1_2_1_10_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-642-73042-9_4"},{"key":"e_1_2_1_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/0022-2836(88)90608-0"},{"key":"e_1_2_1_12_2","doi-asserted-by":"crossref","first-page":"1628","DOI":"10.1016\/S0021-9258(19)77925-3","article-title":"Refined structure of chicken skeletal muscle troponin C in the two\u2010calcium state at 2\u2010\u00c5 resolution","volume":"263","author":"Satyshur K. A.","year":"1988","journal-title":"J. Biol. Chem."},{"key":"e_1_2_1_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/0022-2836(88)90208-2"},{"key":"e_1_2_1_14_2","doi-asserted-by":"publisher","DOI":"10.1002\/prot.340070305"},{"key":"e_1_2_1_15_2","doi-asserted-by":"crossref","first-page":"2638","DOI":"10.1016\/S0021-9258(17)35835-0","article-title":"A model for the Ca2+ \u2010induced conformational transition of the troponin C","volume":"261","author":"Herzberg O.","year":"1986","journal-title":"J. Biol. Chem."},{"key":"e_1_2_1_16_2","first-page":"120","article-title":"Calcium binding to skeletal muscle troponin C and the regulation of muscle contraction","volume":"122","author":"Herzberg O.","year":"1986","journal-title":"Ciba Foundation Symposium"},{"key":"e_1_2_1_17_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi00557a025"},{"key":"e_1_2_1_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/0006-2952(82)90104-6"},{"key":"e_1_2_1_19_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.51.3.290"},{"issue":"9","key":"e_1_2_1_20_2","first-page":"S34","article-title":"Pharmacological modulation of cardiac and vascular contractile protein function","volume":"8","author":"Silver P. J.","year":"1986","journal-title":"J. Cardiovasc. Pharmacol."},{"key":"e_1_2_1_21_2","first-page":"78","article-title":"Effects of new inotropic agents on Ca2++ sensitivity of contractile proteins","volume":"73","author":"R\u00fcegg J. C.","year":"1986","journal-title":"Circulation"},{"key":"e_1_2_1_22_2","first-page":"421","volume-title":"Trends in Medicinal Chemistry","author":"Wentzel B.","year":"1987"},{"key":"e_1_2_1_23_2","first-page":"166","article-title":"New cardiotonic agents\u2013a promising approach for treatment of heart failure","volume":"9","author":"Wenzel B.","year":"1988","journal-title":"TIPS"},{"key":"e_1_2_1_24_2","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.300.6724.551"},{"key":"e_1_2_1_25_2","first-page":"454","article-title":"Selective binding of antipsychotic and other psychoactive agents to the calcium\u2010dependent activator of cyclic nucleotide phosphodiesterase","volume":"208","author":"Levin R. M.","year":"1979","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"e_1_2_1_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/0006-2952(86)90052-3"},{"key":"e_1_2_1_27_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi00455a012"},{"key":"e_1_2_1_28_2","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.1988.sp017256"},{"key":"e_1_2_1_29_2","first-page":"75","article-title":"Modulations by drugs of the relationship between calcium binding to troponin C and tension","volume":"315","author":"Ogawa Y.","year":"1989","journal-title":"Muscle Energ."},{"key":"e_1_2_1_30_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF00582505"},{"key":"e_1_2_1_31_2","first-page":"1013","article-title":"Metofenazate as a more selective calmodulin inhibitor than trifluoperazine","volume":"37","author":"Tkachuk V. A.","year":"1987","journal-title":"Arzneim.\u2010Forsch.\/Drug Res."},{"key":"e_1_2_1_32_2","doi-asserted-by":"publisher","DOI":"10.1016\/0167-4838(84)90006-2"},{"key":"e_1_2_1_33_2","first-page":"509","article-title":"Inhibition of calmodulin by phenothiazines and related drugs: structure\u2010activity relationships","volume":"222","author":"Prozialeck W. C.","year":"1982","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"e_1_2_1_34_2","doi-asserted-by":"publisher","DOI":"10.1016\/0022-5193(83)90424-1"},{"key":"e_1_2_1_35_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-5193(85)80171-5"},{"key":"e_1_2_1_36_2","doi-asserted-by":"publisher","DOI":"10.1002\/prot.340030102"},{"key":"e_1_2_1_37_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF01557722"},{"key":"e_1_2_1_38_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi00276a010"},{"key":"e_1_2_1_39_2","doi-asserted-by":"publisher","DOI":"10.1016\/0014-2999(84)90128-6"},{"key":"e_1_2_1_40_2","first-page":"737","article-title":"Effects on calmodulin of bepridil, an antianginal agent","volume":"230","author":"Itoh H.","year":"1984","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"e_1_2_1_41_2","doi-asserted-by":"publisher","DOI":"10.1016\/0014-2999(86)90604-7"},{"key":"e_1_2_1_42_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI111497"},{"key":"e_1_2_1_43_2","first-page":"502","article-title":"Stimulation of cardiac myofilament force, ATPase activity and troponin C Ca2+ binding by bepridil","volume":"238","author":"Solaro R. J.","year":"1986","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"e_1_2_1_44_2","doi-asserted-by":"crossref","first-page":"9760","DOI":"10.1016\/S0021-9258(19)38736-8","article-title":"Binding of a calcium sensitizer, bepridil, to cardiac troponin C. A fluorescence stopped\u2010flow kinetic, circular dichroism, and proton nuclear magnetic resonance study","volume":"265","author":"MacLachlan L. K.","year":"1990","journal-title":"J. Biol. Chem."},{"key":"e_1_2_1_45_2","first-page":"713","volume":"14","year":"1989","journal-title":"Pimobendan. Drugs of the future"},{"key":"e_1_2_1_46_2","first-page":"1736","article-title":"Effect on contractibility of skinned fibres from mammalian heart and smooth muscle by a new benzimidazole derivative, 4,5\u2010dihydro\u20106\u2010[2\u2010(4\u2010methoxyphenyl)\u20101H\u2010benzimidazole\u20105\u2010yl]\u20105\u2010methyl\u20103\u2010(2H)\u2010pyrdazinone","volume":"34","author":"R\u00fcegg J. C.","year":"1984","journal-title":"Arzneim.\u2010Forsch\/Drug Res."},{"key":"e_1_2_1_47_2","first-page":"561","article-title":"Comparison of the effects of UD\u2010CG 115BS (pimobendane) and milrinone on Ca\u2010activated force and ATPase activity of skinned heart muscle fibers","volume":"46","author":"Fujino K.","year":"1987","journal-title":"Fed. Proc."},{"key":"e_1_2_1_48_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.63.5.911"},{"key":"e_1_2_1_49_2","first-page":"519","article-title":"Different effects of d\u2010and l\u2010pimobendan on cardiac myofilament calcium sensitivity","volume":"247","author":"Fujino K.","year":"1988","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"e_1_2_1_50_2","doi-asserted-by":"publisher","DOI":"10.1016\/0006-291X(87)91592-0"},{"key":"e_1_2_1_51_2","first-page":"1668","article-title":"Effects of the benzimidazole derivatives pimobendan and 2\u2010(4\u2010hydroxyphenyl)\u20105\u2010(5\u2010methyl\u20103\u2010oxo\u20104,5\u2010dihydro\u20102H\u20106\u2010pyridazinyl)benzimidazole\u1e41HCl on phosphodiesterase activity and force of contraction in guinea\u2010pig hearts","volume":"35","author":"Berger C.","year":"1985","journal-title":"Arzneim.\u2010Forsch\/Drug Res."},{"key":"e_1_2_1_52_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-2836(77)80200-3"},{"key":"e_1_2_1_53_2","doi-asserted-by":"publisher","DOI":"10.1002\/mus.880090112"},{"key":"e_1_2_1_54_2","doi-asserted-by":"publisher","DOI":"10.1016\/0014-5793(76)80769-7"},{"key":"e_1_2_1_55_2","doi-asserted-by":"crossref","first-page":"962","DOI":"10.1016\/S0021-9258(19)86127-6","article-title":"The complete amino acid sequence of the Ca2+ \u2010dependent modulator protein (calmodulin) of bovine brain","volume":"255","author":"Watterson D. M.","year":"1980","journal-title":"J. Biol. Chem."},{"key":"e_1_2_1_56_2","unstructured":"Singh U. C. Weiner P. K. Caldwell J. W. Kollman P. A.AMBER (UCSF): Assisted model building with energy refinement Version 3.0. Department of Pharmaceutical Chemistry University of California San Francisco CA 1986."},{"key":"e_1_2_1_57_2","doi-asserted-by":"publisher","DOI":"10.1021\/ja00315a051"},{"key":"e_1_2_1_58_2","doi-asserted-by":"crossref","first-page":"9754","DOI":"10.1016\/S0021-9258(19)38735-6","article-title":"A proton nuclear magnetic resonance and molecular modeling study of cardiac troponin C. Calcium dependence and aromatic spectral assignments","volume":"265","author":"MacLachlan L. K.","year":"1990","journal-title":"J. Biol. Chem."},{"key":"e_1_2_1_59_2","doi-asserted-by":"publisher","DOI":"10.1021\/ja00299a024"},{"key":"e_1_2_1_60_2","first-page":"24","article-title":"Program MOPAC: a general molecular orbital package. QCPE 455 (version 4)","volume":"3","author":"Stewart J. J. P.","year":"1983","journal-title":"QCPE Bulletin"},{"key":"e_1_2_1_61_2","doi-asserted-by":"publisher","DOI":"10.1002\/jcc.540070216"},{"key":"e_1_2_1_62_2","unstructured":"Carlson G. M.Molecular dynamic studies of porcine pancreatic elastase: The native state and complexed to two trifluoroacetyl dipeptide anilide inhibitors. Thesis Texas A&M University 1987."},{"key":"e_1_2_1_63_2","doi-asserted-by":"publisher","DOI":"10.1002\/prot.340060104"},{"key":"e_1_2_1_64_2","doi-asserted-by":"publisher","DOI":"10.1016\/0014-2999(89)90065-4"},{"key":"e_1_2_1_65_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm00399a006"},{"key":"e_1_2_1_66_2","unstructured":"InsightII modelling software Biosym Technologies Inc. San Diego CA."},{"key":"e_1_2_1_67_2","doi-asserted-by":"publisher","DOI":"10.1038\/345182a0"},{"key":"e_1_2_1_68_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi00403a011"},{"key":"e_1_2_1_69_2","doi-asserted-by":"publisher","DOI":"10.1093\/oxfordjournals.jbchem.a122672"},{"key":"e_1_2_1_70_2","doi-asserted-by":"publisher","DOI":"10.1002\/prot.340060409"},{"key":"e_1_2_1_71_2","doi-asserted-by":"publisher","DOI":"10.1016\/0003-9861(90)90032-T"},{"key":"e_1_2_1_72_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)37733-0"},{"key":"e_1_2_1_73_2","doi-asserted-by":"publisher","DOI":"10.1016\/0166-2236(89)90097-0"},{"key":"e_1_2_1_74_2","doi-asserted-by":"crossref","first-page":"19706","DOI":"10.1016\/S0021-9258(19)47170-6","article-title":"Calcium\u2010induced shape change of calmodulin with mastoparan studied by solution X\u2010ray scattering","volume":"264","author":"Yoshino H.","year":"1989","journal-title":"J. Biol. Chem."},{"key":"e_1_2_1_75_2","doi-asserted-by":"publisher","DOI":"10.1002\/prot.340060311"},{"key":"e_1_2_1_76_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi00444a035"},{"key":"e_1_2_1_77_2","doi-asserted-by":"crossref","first-page":"608","DOI":"10.1016\/S0021-9258(17)36135-5","article-title":"Calcium binding to the low affinity sites in troponin C induces conformational changes in the high affinity domain. A possible route of information transfer in activation of muscle contraction","volume":"261","author":"Grabarek Z.","year":"1986","journal-title":"J. Biol. Chem."},{"key":"e_1_2_1_78_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi00453a041"},{"key":"e_1_2_1_79_2","doi-asserted-by":"crossref","first-page":"4953","DOI":"10.1016\/S0021-9258(19)34067-0","article-title":"Ca2+ \u2010dependent interactions between the C\u2010helix of troponin\u2010C and troponin\u2010I","volume":"265","author":"Wang Z.","year":"1990","journal-title":"J. Biol. Chem."}],"container-title":["Proteins: Structure, Function, and Bioinformatics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fprot.340110202","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/prot.340110202","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,22]],"date-time":"2023-10-22T19:56:21Z","timestamp":1698004581000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/prot.340110202"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[1991,10]]},"references-count":78,"journal-issue":{"issue":"2","published-print":{"date-parts":[[1991,10]]}},"alternative-id":["10.1002\/prot.340110202"],"URL":"https:\/\/doi.org\/10.1002\/prot.340110202","archive":["Portico"],"relation":{},"ISSN":["0887-3585","1097-0134"],"issn-type":[{"value":"0887-3585","type":"print"},{"value":"1097-0134","type":"electronic"}],"subject":[],"published":{"date-parts":[[1991,10]]}}}