1 Ocak 2020 Dergi makalesi Açık Erişim

Doruk, Yagmur Umay; Yarparvar, Darya; Akyel, Yasemin Kubra; Gul, Seref; Taskin, Ali Cihan; Yilmaz, Fatma; Baris, Ibrahim; Ozturk, Nuri; Turkay, Metin; Ozturk, Narin; Okyar, Alper; Kavakli, Ibrahim Halil

MARC21 XML

<?xml version='1.0' encoding='UTF-8'?>
<record xmlns="http://www.loc.gov/MARC21/slim">
  <leader>00000nam##2200000uu#4500</leader>
  <datafield tag="245" ind1=" " ind2=" ">
    <subfield code="a">A CLOCK-binding small molecule disrupts the interaction between CLOCK and BMAL1 and enhances circadian rhythm amplitude</subfield>
  </datafield>
  <datafield tag="909" ind1="C" ind2="4">
    <subfield code="p">JOURNAL OF BIOLOGICAL CHEMISTRY</subfield>
    <subfield code="v">295</subfield>
    <subfield code="n">11</subfield>
    <subfield code="c">3518-3531</subfield>
  </datafield>
  <controlfield tag="001">7029</controlfield>
  <datafield tag="980" ind1=" " ind2=" ">
    <subfield code="a">user-tubitak-destekli-proje-yayinlari</subfield>
  </datafield>
  <datafield tag="520" ind1=" " ind2=" ">
    <subfield code="a">Proper function of many physiological processes requires a robust circadian clock. Disruptions of the circadian clock can result in metabolic diseases, mood disorders, and accelerated aging. Therefore, identifying small molecules that specifically modulate regulatory core clock proteins may potentially enable better management of these disorders. In this study, we applied a structure-based molecular-docking approach to find small molecules that specifically bind to the core circadian regulator, the transcription factor circadian locomotor output cycles kaput (CLOCK). We identified 100 candidate molecules by virtual screening of ?2 million small molecules for those predicted to bind closely to the interface in CLOCK that interacts with its transcriptional co-regulator, Brain and muscle Arnt-like protein-1 (BMAL1). Using a mammalian two-hybrid system, real-time monitoring of circadian rhythm in U2OS cells, and various biochemical assays, we tested these compounds experimentally and found one, named CLK8, that specifically bound to and interfered with CLOCK activity. We show that CLK8 disrupts the interaction between CLOCK and BMAL1 and interferes with nuclear translocation of CLOCK both in vivo and in vitro. Results from further experiments indicated that CLK8 enhances the amplitude of the cellular circadian rhythm by stabilizing the negative arm of the transcription/translation feedback loop without affecting period length. Our results reveal CLK8 as a tool for further studies of CLOCK's role in circadian rhythm amplitude regulation and as a potential candidate for therapeutic development to manage disorders associated with dampened circadian rhythms.</subfield>
  </datafield>
  <datafield tag="650" ind1="1" ind2="7">
    <subfield code="2">opendefinition.org</subfield>
    <subfield code="a">cc-by</subfield>
  </datafield>
  <datafield tag="700" ind1=" " ind2=" ">
    <subfield code="u">Koc Univ, Dept Chem &amp; Biol Engn, Rumelifeneri Yolu, TR-34450 Istanbul, Turkey</subfield>
    <subfield code="a">Yarparvar, Darya</subfield>
  </datafield>
  <datafield tag="700" ind1=" " ind2=" ">
    <subfield code="u">Istanbul Univ, Dept Pharmacol, Fac Pharm, TR-34116 Istanbul, Turkey</subfield>
    <subfield code="a">Akyel, Yasemin Kubra</subfield>
  </datafield>
  <datafield tag="700" ind1=" " ind2=" ">
    <subfield code="u">Koc Univ, Dept Chem &amp; Biol Engn, Rumelifeneri Yolu, TR-34450 Istanbul, Turkey</subfield>
    <subfield code="a">Gul, Seref</subfield>
  </datafield>
  <datafield tag="700" ind1=" " ind2=" ">
    <subfield code="u">Koc Univ, Embryo Manipulat Lab, Anim Res Facil, Res Ctr Translat Med, Rumelifeneri yolu, Istanbul, Turkey</subfield>
    <subfield code="a">Taskin, Ali Cihan</subfield>
  </datafield>
  <datafield tag="700" ind1=" " ind2=" ">
    <subfield code="u">Gebze Tech Univ, Dept Mol Biol &amp; Genet, Kocaeli, Turkey</subfield>
    <subfield code="a">Yilmaz, Fatma</subfield>
  </datafield>
  <datafield tag="700" ind1=" " ind2=" ">
    <subfield code="u">Koc Univ, Dept Mol Biol &amp; Genet, Rumelifeneri Yolu, Istanbul, Turkey</subfield>
    <subfield code="a">Baris, Ibrahim</subfield>
  </datafield>
  <datafield tag="700" ind1=" " ind2=" ">
    <subfield code="a">Ozturk, Nuri</subfield>
  </datafield>
  <datafield tag="700" ind1=" " ind2=" ">
    <subfield code="u">Koc Univ, Dept Ind Engn, Rumelifeneri Yolu, Istanbul, Turkey</subfield>
    <subfield code="a">Turkay, Metin</subfield>
  </datafield>
  <datafield tag="700" ind1=" " ind2=" ">
    <subfield code="a">Ozturk, Narin</subfield>
  </datafield>
  <datafield tag="700" ind1=" " ind2=" ">
    <subfield code="u">Istanbul Univ, Dept Pharmacol, Fac Pharm, TR-34116 Istanbul, Turkey</subfield>
    <subfield code="a">Okyar, Alper</subfield>
  </datafield>
  <datafield tag="700" ind1=" " ind2=" ">
    <subfield code="a">Kavakli, Ibrahim Halil</subfield>
  </datafield>
  <datafield tag="980" ind1=" " ind2=" ">
    <subfield code="b">article</subfield>
    <subfield code="a">publication</subfield>
  </datafield>
  <datafield tag="542" ind1=" " ind2=" ">
    <subfield code="l">open</subfield>
  </datafield>
  <datafield tag="100" ind1=" " ind2=" ">
    <subfield code="u">Koc Univ, Dept Mol Biol &amp; Genet, Rumelifeneri Yolu, Istanbul, Turkey</subfield>
    <subfield code="a">Doruk, Yagmur Umay</subfield>
  </datafield>
  <datafield tag="260" ind1=" " ind2=" ">
    <subfield code="c">2020-01-01</subfield>
  </datafield>
  <controlfield tag="005">20210315063332.0</controlfield>
  <datafield tag="909" ind1="C" ind2="O">
    <subfield code="o">oai:zenodo.org:7029</subfield>
    <subfield code="p">user-tubitak-destekli-proje-yayinlari</subfield>
  </datafield>
  <datafield tag="856" ind1="4" ind2=" ">
    <subfield code="z">md5:bec5f126fb02ffe86a55a742676a5dd4</subfield>
    <subfield code="s">322</subfield>
    <subfield code="u">https://aperta.ulakbim.gov.trrecord/7029/files/bib-4dfd9816-902a-4fe6-a2be-68d13ae45f16.txt</subfield>
  </datafield>
  <datafield tag="540" ind1=" " ind2=" ">
    <subfield code="u">http://www.opendefinition.org/licenses/cc-by</subfield>
    <subfield code="a">Creative Commons Attribution</subfield>
  </datafield>
  <datafield tag="024" ind1=" " ind2=" ">
    <subfield code="a">10.1074/jbc.RA119.011332</subfield>
    <subfield code="2">doi</subfield>
  </datafield>
</record>