PMC:5115869 / 23889-25659 JSONTXT

{"target":"http://pubannotation.org/docs/sourcedb/PMC/sourceid/5115869","sourcedb":"PMC","sourceid":"5115869","source_url":"https://www.ncbi.nlm.nih.gov/pmc/5115869","text":"To explore the functional dynamics underlying our data, we compared likelihoods of several kinetic models using hidden Markov modeling (HMM) (Bronson et al., 2009; Nicolai and Sachs, 2013) (Figure 3E; Table 1). Models were globally optimized for smFRET time series from all molecules and fcAMP concentrations and ranked according to their Akaike information criterion (AIC) (Akaike, 1974) (Figure 3F). Consistent with dwell time distributions discussed above, models with two unbound (U1, U2) and two bound (B1, B2) states performed better than models with fewer states, whereas adding additional unbound and bound states did not improve the likelihood. Remarkably, all of the models with two bound states converged to a similar set of rate constants governing an initial binding step followed by a subsequent first order transition (Table 1). The most direct interpretation of this finding is that the CNBD undergoes a reversible conformational change between distinct cAMP-bound conformations. Importantly, simulated data from such a model reproduced the experimentally observed dwell time distributions (Figure 3G).\nTable 1. Kinetic model rate constants. Optimized rate constants (s-1 or M-1s-1) for models shown in Figure 3E. U* and B* denote unbound and bound states, respectively.\nDOI: http://dx.doi.org/10.7554/eLife.20797.013\nModel U1→ B1 B1→ U1 B1→B2 B2→B1 U1→U2 U2→U1 U1→B2 B2→U1\n1 1.3 × 105 0.34 - - - - - -\n2 1.4 × 105 0.91 0.52 0.31 - - - -\n3 1.3 × 105 0.98 0.49 0.23 - - 0.10 × 105 0.04\n4 2.3 × 105 0.95 0.51 0.31 0.04 0.15 - -\n5 2.2 × 105 1.00 0.49 0.25 0.04 0.15 0.14 × 105 0.03\n6 2.4 × 105 1.00 0.48 0.27 0.01 0.04 - -\n7 2.8 × 105 1.11 0.85 0.56 0.17 0.55 - -\nModel U2→B2 B2→U2 U2→U3 U3→U2 B2→B3 B3→B2\n6 0.24 × 105 0.02 - - - -\n7 - - 0.02 0.07 0.03 0.08","divisions":[{"label":"label","span":{"begin":1119,"end":1127}},{"label":"caption","span":{"begin":1128,"end":1333}},{"label":"p","span":{"begin":1128,"end":1286}},{"label":"p","span":{"begin":1287,"end":1333}},{"label":"table","span":{"begin":1334,"end":1676}},{"label":"tr","span":{"begin":1334,"end":1389}},{"label":"th","span":{"begin":1334,"end":1339}},{"label":"p","span":{"begin":1334,"end":1339}},{"label":"th","span":{"begin":1340,"end":1346}},{"label":"p","span":{"begin":1340,"end":1346}},{"label":"th","span":{"begin":1347,"end":1353}},{"label":"p","span":{"begin":1347,"end":1353}},{"label":"th","span":{"begin":1354,"end":1359}},{"label":"p","span":{"begin":1354,"end":1359}},{"label":"th","span":{"begin":1360,"end":1365}},{"label":"p","span":{"begin":1360,"end":1365}},{"label":"th","span":{"begin":1366,"end":1371}},{"label":"p","span":{"begin":1366,"end":1371}},{"label":"th","span":{"begin":1372,"end":1377}},{"label":"p","span":{"begin":1372,"end":1377}},{"label":"th","span":{"begin":1378,"end":1383}},{"label":"p","span":{"begin":1378,"end":1383}},{"label":"th","span":{"begin":1384,"end":1389}},{"label":"p","span":{"begin":1384,"end":1389}},{"label":"tr","span":{"begin":1390,"end":1418}},{"label":"td","span":{"begin":1390,"end":1391}},{"label":"p","span":{"begin":1390,"end":1391}},{"label":"td","span":{"begin":1392,"end":1401}},{"label":"p","span":{"begin":1392,"end":1401}},{"label":"td","span":{"begin":1402,"end":1406}},{"label":"p","span":{"begin":1402,"end":1406}},{"label":"td","span":{"begin":1407,"end":1408}},{"label":"p","span":{"begin":1407,"end":1408}},{"label":"td","span":{"begin":1409,"end":1410}},{"label":"p","span":{"begin":1409,"end":1410}},{"label":"td","span":{"begin":1411,"end":1412}},{"label":"p","span":{"begin":1411,"end":1412}},{"label":"td","span":{"begin":1413,"end":1414}},{"label":"p","span":{"begin":1413,"end":1414}},{"label":"td","span":{"begin":1415,"end":1416}},{"label":"p","span":{"begin":1415,"end":1416}},{"label":"td","span":{"begin":1417,"end":1418}},{"label":"p","span":{"begin":1417,"end":1418}},{"label":"tr","span":{"begin":1419,"end":1453}},{"label":"td","span":{"begin":1419,"end":1420}},{"label":"p","span":{"begin":1419,"end":1420}},{"label":"td","span":{"begin":1421,"end":1430}},{"label":"p","span":{"begin":1421,"end":1430}},{"label":"td","span":{"begin":1431,"end":1435}},{"label":"p","span":{"begin":1431,"end":1435}},{"label":"td","span":{"begin":1436,"end":1440}},{"label":"p","span":{"begin":1436,"end":1440}},{"label":"td","span":{"begin":1441,"end":1445}},{"label":"p","span":{"begin":1441,"end":1445}},{"label":"td","span":{"begin":1446,"end":1447}},{"label":"p","span":{"begin":1446,"end":1447}},{"label":"td","span":{"begin":1448,"end":1449}},{"label":"p","span":{"begin":1448,"end":1449}},{"label":"td","span":{"begin":1450,"end":1451}},{"label":"p","span":{"begin":1450,"end":1451}},{"label":"td","span":{"begin":1452,"end":1453}},{"label":"p","span":{"begin":1452,"end":1453}},{"label":"tr","span":{"begin":1454,"end":1500}},{"label":"td","span":{"begin":1454,"end":1455}},{"label":"p","span":{"begin":1454,"end":1455}},{"label":"td","span":{"begin":1456,"end":1465}},{"label":"p","span":{"begin":1456,"end":1465}},{"label":"td","span":{"begin":1466,"end":1470}},{"label":"p","span":{"begin":1466,"end":1470}},{"label":"td","span":{"begin":1471,"end":1475}},{"label":"p","span":{"begin":1471,"end":1475}},{"label":"td","span":{"begin":1476,"end":1480}},{"label":"p","span":{"begin":1476,"end":1480}},{"label":"td","span":{"begin":1481,"end":1482}},{"label":"p","span":{"begin":1481,"end":1482}},{"label":"td","span":{"begin":1483,"end":1484}},{"label":"p","span":{"begin":1483,"end":1484}},{"label":"td","span":{"begin":1485,"end":1495}},{"label":"p","span":{"begin":1485,"end":1495}},{"label":"td","span":{"begin":1496,"end":1500}},{"label":"p","span":{"begin":1496,"end":1500}},{"label":"tr","span":{"begin":1501,"end":1541}},{"label":"td","span":{"begin":1501,"end":1502}},{"label":"p","span":{"begin":1501,"end":1502}},{"label":"td","span":{"begin":1503,"end":1512}},{"label":"p","span":{"begin":1503,"end":1512}},{"label":"td","span":{"begin":1513,"end":1517}},{"label":"p","span":{"begin":1513,"end":1517}},{"label":"td","span":{"begin":1518,"end":1522}},{"label":"p","span":{"begin":1518,"end":1522}},{"label":"td","span":{"begin":1523,"end":1527}},{"label":"p","span":{"begin":1523,"end":1527}},{"label":"td","span":{"begin":1528,"end":1532}},{"label":"p","span":{"begin":1528,"end":1532}},{"label":"td","span":{"begin":1533,"end":1537}},{"label":"p","span":{"begin":1533,"end":1537}},{"label":"td","span":{"begin":1538,"end":1539}},{"label":"p","span":{"begin":1538,"end":1539}},{"label":"td","span":{"begin":1540,"end":1541}},{"label":"p","span":{"begin":1540,"end":1541}},{"label":"tr","span":{"begin":1542,"end":1594}},{"label":"td","span":{"begin":1542,"end":1543}},{"label":"p","span":{"begin":1542,"end":1543}},{"label":"td","span":{"begin":1544,"end":1553}},{"label":"p","span":{"begin":1544,"end":1553}},{"label":"td","span":{"begin":1554,"end":1558}},{"label":"p","span":{"begin":1554,"end":1558}},{"label":"td","span":{"begin":1559,"end":1563}},{"label":"p","span":{"begin":1559,"end":1563}},{"label":"td","span":{"begin":1564,"end":1568}},{"label":"p","span":{"begin":1564,"end":1568}},{"label":"td","span":{"begin":1569,"end":1573}},{"label":"p","span":{"begin":1569,"end":1573}},{"label":"td","span":{"begin":1574,"end":1578}},{"label":"p","span":{"begin":1574,"end":1578}},{"label":"td","span":{"begin":1579,"end":1589}},{"label":"p","span":{"begin":1579,"end":1589}},{"label":"td","span":{"begin":1590,"end":1594}},{"label":"p","span":{"begin":1590,"end":1594}},{"label":"tr","span":{"begin":1595,"end":1635}},{"label":"td","span":{"begin":1595,"end":1596}},{"label":"p","span":{"begin":1595,"end":1596}},{"label":"td","span":{"begin":1597,"end":1606}},{"label":"p","span":{"begin":1597,"end":1606}},{"label":"td","span":{"begin":1607,"end":1611}},{"label":"p","span":{"begin":1607,"end":1611}},{"label":"td","span":{"begin":1612,"end":1616}},{"label":"p","span":{"begin":1612,"end":1616}},{"label":"td","span":{"begin":1617,"end":1621}},{"label":"p","span":{"begin":1617,"end":1621}},{"label":"td","span":{"begin":1622,"end":1626}},{"label":"p","span":{"begin":1622,"end":1626}},{"label":"td","span":{"begin":1627,"end":1631}},{"label":"p","span":{"begin":1627,"end":1631}},{"label":"td","span":{"begin":1632,"end":1633}},{"label":"p","span":{"begin":1632,"end":1633}},{"label":"td","span":{"begin":1634,"end":1635}},{"label":"p","span":{"begin":1634,"end":1635}},{"label":"tr","span":{"begin":1636,"end":1676}},{"label":"td","span":{"begin":1636,"end":1637}},{"label":"p","span":{"begin":1636,"end":1637}},{"label":"td","span":{"begin":1638,"end":1647}},{"label":"p","span":{"begin":1638,"end":1647}},{"label":"td","span":{"begin":1648,"end":1652}},{"label":"p","span":{"begin":1648,"end":1652}},{"label":"td","span":{"begin":1653,"end":1657}},{"label":"p","span":{"begin":1653,"end":1657}},{"label":"td","span":{"begin":1658,"end":1662}},{"label":"p","span":{"begin":1658,"end":1662}},{"label":"td","span":{"begin":1663,"end":1667}},{"label":"p","span":{"begin":1663,"end":1667}},{"label":"td","span":{"begin":1668,"end":1672}},{"label":"p","span":{"begin":1668,"end":1672}},{"label":"td","span":{"begin":1673,"end":1674}},{"label":"p","span":{"begin":1673,"end":1674}},{"label":"td","span":{"begin":1675,"end":1676}},{"label":"p","span":{"begin":1675,"end":1676}},{"label":"tr","span":{"begin":1677,"end":1718}},{"label":"th","span":{"begin":1677,"end":1682}},{"label":"p","span":{"begin":1677,"end":1682}},{"label":"th","span":{"begin":1683,"end":1688}},{"label":"p","span":{"begin":1683,"end":1688}},{"label":"th","span":{"begin":1689,"end":1694}},{"label":"p","span":{"begin":1689,"end":1694}},{"label":"th","span":{"begin":1695,"end":1700}},{"label":"p","span":{"begin":1695,"end":1700}},{"label":"th","span":{"begin":1701,"end":1706}},{"label":"p","span":{"begin":1701,"end":1706}},{"label":"th","span":{"begin":1707,"end":1712}},{"label":"p","span":{"begin":1707,"end":1712}},{"label":"th","span":{"begin":1713,"end":1718}},{"label":"p","span":{"begin":1713,"end":1718}},{"label":"tr","span":{"begin":1719,"end":1744}},{"label":"td","span":{"begin":1719,"end":1720}},{"label":"p","span":{"begin":1719,"end":1720}},{"label":"td","span":{"begin":1721,"end":1731}},{"label":"p","span":{"begin":1721,"end":1731}},{"label":"td","span":{"begin":1732,"end":1736}},{"label":"p","span":{"begin":1732,"end":1736}},{"label":"td","span":{"begin":1737,"end":1738}},{"label":"p","span":{"begin":1737,"end":1738}},{"label":"td","span":{"begin":1739,"end":1740}},{"label":"p","span":{"begin":1739,"end":1740}},{"label":"td","span":{"begin":1741,"end":1742}},{"label":"p","span":{"begin":1741,"end":1742}},{"label":"td","span":{"begin":1743,"end":1744}},{"label":"p","span":{"begin":1743,"end":1744}},{"label":"td","span":{"begin":1745,"end":1746}},{"label":"p","span":{"begin":1745,"end":1746}},{"label":"td","span":{"begin":1747,"end":1748}},{"label":"p","span":{"begin":1747,"end":1748}},{"label":"td","span":{"begin":1749,"end":1750}},{"label":"p","span":{"begin":1749,"end":1750}},{"label":"td","span":{"begin":1751,"end":1755}},{"label":"p","span":{"begin":1751,"end":1755}},{"label":"td","span":{"begin":1756,"end":1760}},{"label":"p","span":{"begin":1756,"end":1760}},{"label":"td","span":{"begin":1761,"end":1765}},{"label":"p","span":{"begin":1761,"end":1765}}],"tracks":[{"project":"2_test","denotations":[{"id":"27858593-20006957-27104447","span":{"begin":158,"end":162},"obj":"20006957"}],"attributes":[{"subj":"27858593-20006957-27104447","pred":"source","obj":"2_test"}]},{"project":"MyTest","denotations":[{"id":"27858593-20006957-27104447","span":{"begin":158,"end":162},"obj":"20006957"}],"namespaces":[{"prefix":"_base","uri":"https://www.uniprot.org/uniprot/testbase"},{"prefix":"UniProtKB","uri":"https://www.uniprot.org/uniprot/"},{"prefix":"uniprot","uri":"https://www.uniprot.org/uniprotkb/"}],"attributes":[{"subj":"27858593-20006957-27104447","pred":"source","obj":"MyTest"}]}],"config":{"attribute types":[{"pred":"source","value type":"selection","values":[{"id":"2_test","color":"#daec93","default":true},{"id":"MyTest","color":"#e493ec"}]}]}}