0 3 Two two CD 4 12 distinct distinct JJ 13 19 signal signal NN 20 32 transmission transmission NN 33 41 pathways pathway NNS 42 44 in in IN 45 46 T t NN 47 58 lymphocytes lymphocyte NNS 59 62 are be VBP 63 72 inhibited inhibit VBN 73 75 by by IN 76 85 complexes complex NNS 86 92 formed form VBN 93 100 between between IN 101 103 an an DT 104 116 immunophilin immunophilin NN 117 120 and and CC 121 127 either either CC 128 133 FK506 FK506 NNP 134 136 or or CC 137 146 rapamycin rapamycin NN 146 147 . . . 149 162 Proliferation proliferation NN 163 166 and and CC 167 178 immunologic immunologic JJ 179 187 function function NN 188 190 of of IN 191 192 T t NN 193 204 lymphocytes lymphocyte NNS 205 208 are be VBP 209 218 initiated initiate VBN 219 221 by by IN 222 229 signals signal NNS 230 234 from from IN 235 238 the the DT 239 246 antigen antigen NN 247 255 receptor receptor NN 256 260 that that WDT 261 264 are be VBP 265 274 inhibited inhibit VBN 275 277 by by IN 278 281 the the DT 282 299 immunosuppressant immunosuppressant JJ 300 305 FK506 FK506 NNP 306 309 but but CC 310 313 not not RB 314 316 by by IN 317 320 its its PRP$ 321 331 structural structural JJ 332 338 analog analog NN 338 339 , , , 340 349 rapamycin rapamycin NN 349 350 . . . 351 353 On on IN 354 357 the the DT 358 363 other other JJ 364 368 hand hand NN 368 369 , , , 370 381 interleukin interleukin NN 382 383 2 2 CD 384 385 ( ( ( 385 398 IL-2)-induced il-2)-induced JJ 399 406 signals signal NNS 407 410 are be VBP 411 418 blocked block VBN 419 421 by by IN 422 431 rapamycin rapamycin NN 432 435 but but CC 436 439 not not RB 440 442 by by IN 443 448 FK506 FK506 NNP 448 449 . . . 450 460 Remarkably remarkably RB 460 461 , , , 462 467 these these DT 468 471 two two CD 472 477 drugs drug NNS 478 485 inhibit inhibit VBP 486 490 each each DT 491 496 other other JJ 496 498 ’s 's POS 499 506 actions action NNS 506 507 , , , 508 515 raising raise VBG 516 519 the the DT 520 531 possibility possibility NN 532 536 that that IN 537 541 both both DT 542 545 act act VBP 546 548 by by IN 549 554 means mean NNS 555 557 of of IN 558 559 a a DT 560 566 common common JJ 567 579 immunophilin immunophilin NN 580 581 ( ( ( 581 598 immunosuppressant immunosuppressant NN 599 606 binding binding NN 607 614 protein protein NN 614 615 ) ) ) 615 616 . . . 617 619 We we PRP 620 624 find find VBP 625 629 that that IN 630 633 the the DT 634 646 dissociation dissociation NN 647 655 constant constant NN 656 658 of of IN 659 668 rapamycin rapamycin NN 669 671 to to TO 672 675 the the DT 676 681 FK506 FK506 NNP 682 689 binding binding NN 690 697 protein protein NN 698 702 FKBP FKBP NNP 703 704 ( ( ( 704 706 Kd Kd NNP 707 708 = = SYM 709 712 0.2 0.2 CD 713 715 nM nM NNP 715 716 ) ) ) 717 719 is be VBZ 720 725 close close JJ 726 728 to to TO 729 732 the the DT 733 745 dissociation dissociation NN 746 754 constant constant NN 755 757 of of IN 758 763 FK506 FK506 NNP 764 766 to to TO 767 771 FKBP FKBP NNP 772 773 ( ( ( 773 775 Kd Kd NNP 776 777 = = SYM 778 781 0.4 0.4 CD 782 784 nM nM NNP 784 785 ) ) ) 786 789 and and CC 790 792 to to TO 793 798 their their PRP$ 799 808 effective effective JJ 809 817 biologic biologic JJ 818 828 inhibitory inhibitory JJ 829 843 concentrations concentration NNS 843 844 . . . 845 852 However however RB 852 853 , , , 854 856 an an DT 857 863 excess excess NN 864 866 of of IN 867 876 rapamycin rapamycin NN 877 879 is be VBZ 880 886 needed need VBN 887 889 to to TO 890 896 revert revert VB 897 911 FK506-mediated fk506-mediated JJ 912 922 inhibition inhibition NN 923 925 of of IN 926 930 IL-2 il-2 NN 931 941 production production NN 941 942 , , , 943 952 apoptosis apoptosis NN 952 953 , , , 954 957 and and CC 958 973 transcriptional transcriptional JJ 974 984 activation activation NN 985 987 of of IN 988 993 NF-AT NF-AT NNP 993 994 , , , 995 996 a a DT 997 1012 T-cell-specific t-cell-specific JJ 1013 1026 transcription transcription NN 1027 1033 factor factor NN 1034 1043 necessary necessary JJ 1044 1047 for for IN 1048 1052 IL-2 il-2 NN 1053 1057 gene gene NN 1058 1068 activation activation NN 1068 1069 . . . 1070 1079 Similarly similarly RB 1079 1080 , , , 1081 1083 an an DT 1084 1090 excess excess NN 1091 1093 of of IN 1094 1099 FK506 FK506 NNP 1100 1102 is be VBZ 1103 1109 needed need VBN 1110 1112 to to TO 1113 1119 revert revert VB 1120 1138 rapamycin-mediated rapamycin-mediated JJ 1139 1149 inhibition inhibition NN 1150 1152 of of IN 1153 1165 IL-2-induced il-2-induced JJ 1166 1179 proliferation proliferation NN 1179 1180 . . . 1181 1184 The the DT 1185 1189 drug drug NN 1190 1204 concentrations concentration NNS 1205 1213 required require VBN 1214 1217 for for IN 1218 1228 antagonism antagonism NN 1229 1232 may may MD 1233 1235 be be VB 1236 1245 explained explain VBN 1246 1248 by by IN 1249 1252 the the DT 1253 1261 relative relative JJ 1262 1270 affinity affinity NN 1271 1273 of of IN 1274 1277 the the DT 1278 1283 drugs drug NNS 1284 1286 to to TO 1286 1287 , , , 1288 1291 and and CC 1292 1294 by by IN 1295 1298 the the DT 1299 1308 abundance abundance NN 1309 1311 of of IN 1311 1312 , , , 1313 1316 the the DT 1317 1329 immunophilin immunophilin NN 1330 1334 FKBP FKBP NNP 1334 1335 . . . 1336 1340 FKBP FKBP NNP 1341 1344 has have VBZ 1345 1349 been be VBN 1350 1355 shown show VBN 1356 1358 to to TO 1359 1367 catalyze catalyze VB 1368 1371 the the DT 1372 1387 interconversion interconversion NN 1388 1390 of of IN 1391 1394 the the DT 1395 1399 cis- cis- NN 1400 1403 and and CC 1404 1418 trans-rotamers trans-rotamer NNS 1419 1421 of of IN 1422 1425 the the DT 1426 1441 peptidyl-prolyl peptidyl-prolyl JJ 1442 1447 amide amide NN 1448 1452 bond bond NN 1453 1455 of of IN 1456 1463 peptide peptide NN 1464 1474 substrates substrate NNS 1474 1475 ; ; : 1476 1480 here here RB 1481 1483 we we PRP 1484 1488 show show VBP 1489 1493 that that IN 1494 1503 rapamycin rapamycin NN 1503 1504 , , , 1505 1509 like like IN 1510 1515 FK506 FK506 NNP 1515 1516 , , , 1517 1519 is be VBZ 1520 1521 a a DT 1522 1528 potent potent JJ 1529 1538 inhibitor inhibitor NN 1539 1541 of of IN 1542 1545 the the DT 1546 1554 rotamase rotamase NN 1555 1563 activity activity NN 1564 1566 of of IN 1567 1571 FKBP FKBP NNP 1572 1573 ( ( ( 1573 1575 Ki Ki NNP 1576 1577 = = SYM 1578 1581 0.2 0.2 CD 1582 1584 nM nM NNP 1584 1585 ) ) ) 1585 1586 . . . 1587 1594 Neither neither CC 1595 1599 FKBP FKBP NNP 1600 1607 binding binding NN 1608 1611 nor nor CC 1612 1622 inhibition inhibition NN 1623 1625 of of IN 1626 1634 rotamase rotamase NN 1635 1643 activity activity NN 1644 1646 of of IN 1647 1651 FKBP FKBP NNP 1652 1657 alone alone RB 1658 1660 is be VBZ 1661 1671 sufficient sufficient JJ 1672 1674 to to TO 1675 1682 explain explain VB 1683 1686 the the DT 1687 1695 biologic biologic JJ 1696 1703 actions action NNS 1704 1706 of of IN 1707 1712 these these DT 1713 1718 drugs drug NNS 1718 1719 . . . 1720 1726 Rather rather RB 1726 1727 , , , 1728 1733 these these DT 1734 1742 findings finding NNS 1743 1750 suggest suggest VBP 1751 1755 that that IN 1756 1768 immunophilin immunophilin NN 1769 1774 bound bind VBD 1775 1777 to to TO 1778 1783 FK506 FK506 NNP 1784 1794 interferes interfere VBZ 1795 1799 with with IN 1800 1807 antigen antigen NN 1808 1824 receptor-induced receptor-induced JJ 1825 1832 signals signal NNS 1832 1833 , , , 1834 1839 while while IN 1840 1849 rapamycin rapamycin NN 1850 1855 bound bind VBD 1856 1858 to to TO 1859 1862 the the DT 1863 1875 immunophilin immunophilin NN 1876 1886 interferes interfere VBZ 1887 1891 with with IN 1892 1904 IL-2-induced il-2-induced JJ 1905 1912 signals signal NNS 1912 1913 . . .