281:
BET proteins, giving BD-specific inhibition. The BD-ET bump-and-hole pairs were used to show that selective inhibition of BD1 in a BET protein disrupts chromatin engagement. Recently, the Ciulli group developed a new bump-and-hole pair consisting of BET mutants with a Leu to Val mutation in a BD and the bumped small-molecule inhibitor 9-ME-1. This bumped inhibitor was found to have an IC50 of 200nM and over 100-fold specificity for the L/V BET mutant BD over wild type BDs. This bump-and-hole pair allowed selective inhibition of specific BDs in specific BET proteins, elucidating their role in human cells. It was found that while BD1 is important for chromatin localization of BET proteins, BD2 regulates gene expression by binding and recruiting non-histone acetylated proteins, such as
20:
339:, is initially glycosylated. Once the glycosylated NONOate enters cells and is exposed to glycosidases, NO is released. However, non-tissue-specific systemic release of NO, which can reduce therapeutic efficiency and cause harmful side effects, from these pro-drugs was evident due to widespread distribution of endogenous glycosidases. To get around this, Hou et al. developed a bumped pro-drug via
102:
167:
397:-GalNac analogs and double hole-modified I253A/L310A mutant GalNac Ts (BH GalNac Ts). The UDP-alkyne analogs were specific to complementary BH GalNac Ts, which were shown to maintain the biochemical competence of wild type GalNac Ts, with regards to structure, localization, and substrate specificity. This bump-and-hole pair attached a bio-orthogonal label, visualizable through
293:
256:
369:
207:
While bumped ATM analogs can help deconvolute kinase substrate profiles, one drawback of this strategy is the cell impermeability of the bumped analogs. To get around this, the Shokat group demonstrated that a bumped ATP analog, kinetin ATP or KTP, could be synthesized endogenously in cells cultured
191:
lab has developed bump-and-hole pairs using kinase mutants with bulky "gatekeeper" residues in the ATP-binding pocket replaced by Gly or Ala, and bulky ATP analogs. In early work, v-Src kinase I338A/G mutants were shown to accept -labeled bumped N-cyclopentyl and N-benzyl ATP analogs as alternative
343:
of the O6 of the galactose moiety of galactosyl-NONOate. They engineered a corresponding hole-modified β-galactosidase mutant, A4-β-GalH363A with specificity for the bumped galactosyl-NONOate. The bumped pro-drug evaded cleavage by wild type β-galactosidase due to the methylated O6 of the galactose
275:
Recently, four members of the BET family, BRD2, 3, 4, and BRDT, each containing two bromodomains, were identified as important regulators of transcription. In order to probe bromodomain-specific functions of members of the BET family, small-molecule inhibitors JQ1 and I-BET were developed, but they
125:
of cyclophilin. This first bump-and-hole pair was engineered to improve the binding efficiency between wild type cyclosporin A and cyclophilin, thereby giving more efficient CID. The bumped cyclosporin A was found to interact efficiently with the hole-modified cyclophilin mutant, but not endogenous
348:
of glycosidases. NO was released in tissues only in the presence of both the bumped galactosyl-NONOate and the hole-modified β-galactosidase mutant, giving spatiotemporal control of delivery. Hou et al. found markedly increased therapeutic efficiency of NO delivery via the bump-and-hole engineered
280:
produced bump-and-hole pairs consisting of ET, a derivative of I-BET with an ethyl bump, and different members of the BET family with an L94A mutation in their BD1. ET was found to have a 160-fold greater specificity for hole-modified BD1 of BET mutants compared to compared to the BDs of wild type
57:
with an amino acid substitution from a larger to smaller residue, e.g. glycine or alanine, at the cofactor binding site. The designed ligand/inhibitor has specificity for the engineered protein due to steric complementarity, but not the native counterpart due to steric interference.
392:
Further, GalNac transferase knockout strategies are ineffective because the activity of isoforms in the family is both redundant and competitive, such that compensation occurs upon KO. Recently, Schumann et al. applied the bump-and-hole strategy to engineer bumped alkyne-containing
388:) of its substrates, using UDP-GalNac as a cofactor. Like kinases, substrate profiling for specific isoforms of GalNac Ts has been difficult to achieve. The absence of a glycosylation consensus sequence and the variability of glycan elaboration pose a challenge to studying O-GalNac
157:
As structural information about protein-ligand interfaces have become available, bump-and-hole pairs have been used to elucidate the substrates of specific proteins from various protein classes, as well as develop orthogonal neoenzyme-neosubstrate therapeutics.
48:
complementarity while maintaining biochemical competence and orthogonality to the wild type pair. Typically, a "bumped" ligand/inhibitor analog is designed to bind a corresponding "hole-modified" protein. Bumped ligands are commonly bulkier derivatives of a
39:
in a protein family without perturbing the other members of the family. The unattainability of isoform-selective inhibition due to structural homology in protein families is a major challenge of chemical genetics. With the bump-and-hole approach, a
243:-ButPhe-PP1 caused the reversal of transformation, suggesting inhibition of the kinase mutant. Later, the group developed bumped inhibitors 1-naphthyl PP1 (NA-PP1) and 1-methylnaphthyl PP1 (MN-PP1), which inhibited hole-modified yeast kinases with
186:
substrate proteins. Kinases play critical roles in complex cell signaling networks. Conserved ATP binding sites and similar catalytic mechanisms pose a challenge to selectively inhibiting a particular kinase to determine its function.
1350:
Schumann, Benjamin; Malaker, Stacy Alyse; Wisnovsky, Simon Peter; Debets, Marjoke
Froukje; Agbay, Anthony John; Fernandez, Daniel; Wagner, Lauren Jan Sarbo; Lin, Liang; Li, Zhen; Choi, Junwon; Fox, Douglas Michael (April 2020).
919:
Bishop, Anthony C.; Ubersax, Jeffrey A.; Petsch, Dejah T.; Matheos, Dina P.; Gray, Nathanael S.; Blethrow, Justin; Shimizu, Eiji; Tsien, Joe Z.; Schultz, Peter G.; Rose, Mark D.; Wood, John L. (September 2000).
1166:
Filippakopoulos, Panagis; Qi, Jun; Picaud, Sarah; Shen, Yao; Smith, William B.; Fedorov, Oleg; Morse, Elizabeth M.; Keates, Tracey; Hickman, Tyler T.; Felletar, Ildiko; Philpott, Martin (December 2010).
1051:
Filippakopoulos, Panagis; Qi, Jun; Picaud, Sarah; Shen, Yao; Smith, William B.; Fedorov, Oleg; Morse, Elizabeth M.; Keates, Tracey; Hickman, Tyler T.; Felletar, Ildiko; Philpott, Martin (December 2010).
192:
cofactors to radiolabel its substrates. Only the mutant kinase was able to bind the bumped ATP analogs, allowing labeling of substrates specific to the engineered v-Src kinase. Purification and
235:-ButPhe-PP1 was developed for selective inhibition; steric bulk precluded binding to the wild type v-Src kinase. In mammalian cell lines, active v-Src kinase is required for transformation by
105:
The first reported bump-and-hole pair. Hole-modified S99T/F113A mutant cyclophilin has an expanded hydrophobic pocket to accept a methyl bump in cyclosporin A analog MeIle11CsA.
548:
Belshaw, Peter J.; Schoepfer, Joseph G.; Liu, Karen-Qianye; Morrison, Kim L.; Schreiber, Stuart L. (1995-10-16). "Rational Design of
Orthogonal Receptor–Ligand Combinations".
986:
Baud, M. G. J.; Lin-Shiao, E.; Cardote, T.; Tallant, C.; Pschibul, A.; Chan, K.-H.; Zengerle, M.; Garcia, J. R.; Kwan, T. T.- L.; Ferguson, F. M.; Ciulli, A. (2014-10-31).
223:
The Shokat group also applied the bump-and-hole approach to develop selective, cell-permeable bumped inhibitors of mutant kinases. For the I338G v-Src kinase, a 4-amino-l-
1232:
Runcie, A. C.; Zengerle, M.; Chan, K.-H.; Testa, A.; van
Beurden, L.; Baud, M. G. J.; Epemolu, O.; Ellis, L. C. J.; Read, K. D.; Coulthard, V.; Brien, A. (2018).
470:
Kast, Peter; Hennecke, Hauke (November 1991). "Amino acid substrate specificity of
Escherichia coli phenylalanyl-tRNA synthetase altered by distinct mutations".
766:
Ubersax, Jeffrey A.; Woodbury, Erika L.; Quang, Phuong N.; Paraz, Maria; Blethrow, Justin D.; Shah, Kavita; Shokat, Kevan M.; Morgan, David O. (October 2003).
401:, on the substrates of distinct GalNac T isoforms, deconvolving substrate profiles while displaying complexity of glycan elaboration in the secretory pathway.
98:-FluoroPhe in translation, demonstrating that steric manipulation can successfully broaden substrate scope, even for the highly specific aminoacyl synthetase.
1292:
Hou, Jingli; Pan, Yiwa; Zhu, Dashuai; Fan, Yueyuan; Feng, Guowei; Wei, Yongzhen; Wang, He; Qin, Kang; Zhao, Tiechan; Yang, Qiang; Zhu, Yan (February 2019).
1117:
Shi, Jian; Wang, Yifan; Zeng, Lei; Wu, Yadi; Deng, Jiong; Zhang, Qiang; Lin, Yiwei; Li, Junlin; Kang, Tiebang; Tao, Min; Rusinova, Elena (February 2014).
196:
yielded the substrates of v-Src kinase. Hole-modified kinase and bumped ATP analog pairs enabled substrate profiling of several other kinases, including
665:
Lee, Minjung; Li, Jia; Liang, Yi; Ma, Guolin; Zhang, Jixiang; He, Lian; Liu, Yuliang; Li, Qian; Li, Minyong; Sun, Deqiang; Zhou, Yubin (2017-04-05).
259:
The bumped ET inhibitor has selectivity for L94A BET BD due to steric complementarity. The un-bumped I-BET inhibitor would promiscuously bind BDs.
829:
Hertz, Nicholas T.; Berthet, Amandine; Sos, Martin L.; Thorn, Kurt S.; Burlingame, Al L.; Nakamura, Ken; Shokat, Kevan M. (August 2013).
170:
The bumped ATP analog N6-cyclopentyl ATP cannot bind wild type v-Src kinase, but can bind its bump-and-hole pair, I338G v-Src kinase.
267:(Bromodomains and Extra Terminal) family of proteins contain conserved motifs known as bromodomains (BDs) responsible for recognizing
312:
122:
372:
Hole-modified BH GalNac-Ts paired with UDP-GalNac analogs to tag GalNac T substrates to be visualized with click chemistry.
630:
Belshaw, Peter J.; Schreiber, Stuart L. (February 1997). "Cell-Specific
Calcineurin Inhibition by a Modified Cyclosporin".
296:
Schematic of bumped pro-drug and hole-modified enzyme, releasing the drug only in the presence of the bump-and-hole pair.
138:
in a cell- and tissue-specific manner. More recently, this first bump-and-hole pair was used to induce the assembly of
41:
220:(PD). In the context of PD, the mutant PINK1-KTP pair represents an orthogonal neoenzyme-neosubstrate therapeutic.
139:
1119:"Disrupting the Interaction of BRD4 with Diacetylated Twist Suppresses Tumorigenesis in Basal-like Breast Cancer"
197:
193:
71:
216:
kinase mutant, which is otherwise inactive in the absence of the bumped analog. Inactive PINK1 is implicated in
1413:
878:
Bishop, Anthony C.; Shah, Kavita; Liu, Yi; Witucki, Laurie; Kung, Chi-yun; Shokat, Kevan M. (February 1998).
1418:
50:
385:
217:
179:
94:
showed that a hole-modified A294G phenylalanine tRNA synthetase mutant was able to incorporate the bumped
381:
79:
1180:
1065:
999:
933:
779:
584:
282:
394:
354:
1353:"Bump-and-Hole Engineering Identifies Specific Substrates of Glycosyltransferases in Living Cells"
1329:
965:
811:
236:
54:
988:"A bump-and-hole approach to engineer controlled selectivity of BET bromodomain chemical probes"
831:"A Neo-Substrate that Amplifies Catalytic Activity of Parkinson's-Disease-Related Kinase PINK1"
86:-FluoroPhe due to steric crowding from the hydroxymethylene of S294. Later work in the labs of
1408:
1384:
1321:
1313:
1271:
1253:
1214:
1196:
1148:
1099:
1081:
1033:
1015:
957:
949:
901:
860:
803:
795:
748:
704:
686:
647:
612:
604:
565:
530:
522:
487:
452:
143:
131:
32:
505:
Liu, Chang C.; Schultz, Peter G. (2010-06-07). "Adding New
Chemistries to the Genetic Code".
1374:
1364:
1305:
1261:
1245:
1204:
1188:
1138:
1130:
1089:
1073:
1023:
1007:
941:
891:
850:
842:
787:
738:
694:
678:
639:
596:
557:
514:
479:
442:
434:
345:
110:
91:
87:
67:
1234:"Optimization of a "bump-and-hole" approach to allele-selective BET bromodomain inhibition"
78:-FluoroPhe, a slightly bumped phenylalanine analog which is cytotoxic when incorporated in
19:
518:
398:
319:
was paired with a bumped galactosyl-pro-drug. Jingli Hou and colleagues sought to deliver
304:
183:
117:
small-molecule with an Ile replacing Val at position 11, and a hole-modified (S99T/F113A)
36:
1184:
1069:
1003:
937:
783:
1379:
1352:
1266:
1233:
1209:
1168:
1143:
1118:
1094:
1053:
1028:
987:
855:
830:
699:
666:
447:
422:
328:
316:
277:
239:. In cell lines expressing I338G v-Src kinase and transfected with RSV, treatment with
45:
896:
879:
743:
726:
725:
Liu, Yi; Shah, Kavita; Yang, Feng; Witucki, Laurie; Shokat, Kevan M. (February 1998).
600:
276:
lacked inter- and intra-BET (between BDs on the same protein) selectivity. The lab of
1402:
483:
308:
1333:
1294:"Targeted delivery of nitric oxide via a 'bump-and-hole'-based enzyme–prodrug pair"
1293:
969:
815:
438:
389:
324:
320:
315:. In a recent therapeutic application of the bump-and-hole method, a hole-modified
188:
1369:
340:
300:
268:
264:
127:
118:
114:
846:
101:
1309:
1134:
727:"Engineering Src family protein kinases with unnatural nucleotide specificity"
166:
1317:
1257:
1200:
1085:
1019:
953:
799:
767:
690:
651:
608:
569:
526:
1011:
585:"Chemical genetics resulting from a passion for synthetic organic chemistry"
1388:
1325:
1275:
1218:
1152:
1103:
1037:
961:
864:
807:
708:
561:
534:
456:
921:
905:
752:
616:
491:
82:. The A294S mutant strain was able to incorporate Phe, but not the bumped
922:"A chemical switch for inhibitor-sensitive alleles of any protein kinase"
682:
350:
1192:
1077:
880:"Design of allele-specific inhibitors to probe protein kinase signaling"
791:
1249:
336:
332:
272:
209:
643:
945:
175:
135:
423:"The Bump-and-Hole Tactic: Expanding the Scope of Chemical Genetics"
368:
323:, an important messenger for promoting tissue growth processes like
292:
255:
667:"Engineered Split-TET2 Enzyme for Inducible Epigenetic Remodeling"
367:
291:
254:
213:
201:
165:
100:
18:
244:
70:
strains which carried an A294S mutant version of phenylalanine
66:
Inspiration for the bump-and-hole method was drawn from mutant
380:
Acetylgalactosaminyl transferase (GalNac Ts) family transfers
349:
system, compared to the unmodified pro-drug, in rat hindlimb
331:, in a spatiotemporally controlled manner. They opted for a
303:
are a family of enzymes that catalyzes the hydrolysis of
231:-methylphenyl)pyrazolopyrimidine (PP1) derivative called
126:
cyclophilin. The orthogonal CID pair was used to inhibit
44:
interface is engineered to achieve selectivity through
550:Angewandte Chemie International Edition in English
53:of the target protein. Hole-modified proteins are
142:dioxygenase in cells for temporally controlled
768:"Targets of the cyclin-dependent kinase Cdk1"
8:
109:The first bump-and-hole pair, developed by
1169:"Selective inhibition of BET bromodomains"
1054:"Selective inhibition of BET bromodomains"
311:proteins, one of the most common forms of
1378:
1368:
1265:
1208:
1142:
1093:
1027:
895:
854:
742:
698:
446:
671:Journal of the American Chemical Society
632:Journal of the American Chemical Society
307:. These enzymes can cleave glycans from
247:values in low nanomolar concentrations.
410:
335:system, wherein the NO-releasing drug,
212:. Once synthesized, it can activate a
123:chemical inducer of dimerization (CID)
1345:
1343:
1287:
1285:
981:
979:
519:10.1146/annurev.biochem.052308.105824
7:
720:
718:
589:Bioorganic & Medicinal Chemistry
416:
414:
583:Schreiber, Stuart L. (1998-08-01).
364:-Acetylgalactosaminyl transferases
23:Schematic of bump-and-hole method.
14:
421:Islam, Kabirul (October 2018).
313:post-translational modification
134:of nuclear factor of activated
439:10.1016/j.chembiol.2018.07.001
1:
897:10.1016/S0960-9822(98)70198-8
744:10.1016/S1074-5521(98)90143-0
601:10.1016/S0968-0896(98)00126-6
507:Annual Review of Biochemistry
113:and colleagues, was a bumped
1370:10.1016/j.molcel.2020.03.030
484:10.1016/0022-2836(91)90740-W
472:Journal of Molecular Biology
384:to the Ser/Thr side chains (
121:mutant. Cyclosporin A is a
1435:
847:10.1016/j.cell.2013.07.030
140:ten-eleven translocation 2
1310:10.1038/s41589-018-0190-5
1135:10.1016/j.ccr.2014.01.028
74:and survived exposure to
16:Tool in chemical genetics
35:for studying a specific
1298:Nature Chemical Biology
1012:10.1126/science.1249830
731:Chemistry & Biology
55:recombinantly expressed
562:10.1002/anie.199521291
386:O-linked glycosylation
373:
297:
283:transcription factors.
271:lysine on nucleosomal
260:
171:
106:
24:
427:Cell Chemical Biology
382:N-Acetylgalactosamine
371:
295:
258:
169:
104:
22:
683:10.1021/jacs.7b01459
29:bump-and-hole method
1193:10.1038/nature09504
1185:2010Natur.468.1067F
1179:(7327): 1067–1073.
1078:10.1038/nature09504
1070:2010Natur.468.1067F
1064:(7327): 1067–1073.
1004:2014Sci...346..638B
938:2000Natur.407..395B
792:10.1038/nature02062
784:2003Natur.425..859U
355:acute kidney injury
218:Parkinson's disease
194:MS-based proteomics
1363:(5): 824–834.e15.
1250:10.1039/C7SC02536J
374:
344:moiety and strict
298:
261:
237:Rous sarcoma virus
172:
107:
25:
998:(6209): 638–641.
932:(6802): 395–401.
778:(6960): 859–864.
677:(13): 4659–4662.
644:10.1021/ja9636146
556:(19): 2129–2132.
433:(10): 1171–1184.
182:as a cofactor to
144:DNA demethylation
132:dephosphorylation
33:chemical genetics
1426:
1393:
1392:
1382:
1372:
1347:
1338:
1337:
1289:
1280:
1279:
1269:
1244:(9): 2452–2468.
1238:Chemical Science
1229:
1223:
1222:
1212:
1163:
1157:
1156:
1146:
1114:
1108:
1107:
1097:
1048:
1042:
1041:
1031:
983:
974:
973:
946:10.1038/35030148
916:
910:
909:
899:
875:
869:
868:
858:
826:
820:
819:
763:
757:
756:
746:
722:
713:
712:
702:
662:
656:
655:
638:(7): 1805–1806.
627:
621:
620:
595:(8): 1127–1152.
580:
574:
573:
545:
539:
538:
502:
496:
495:
467:
461:
460:
450:
418:
346:regioselectivity
305:glycosidic bonds
111:Stuart Schreiber
92:David A. Tirrell
88:Peter G. Schultz
1434:
1433:
1429:
1428:
1427:
1425:
1424:
1423:
1414:Homology theory
1399:
1398:
1397:
1396:
1349:
1348:
1341:
1291:
1290:
1283:
1231:
1230:
1226:
1165:
1164:
1160:
1116:
1115:
1111:
1050:
1049:
1045:
985:
984:
977:
918:
917:
913:
884:Current Biology
877:
876:
872:
828:
827:
823:
765:
764:
760:
724:
723:
716:
664:
663:
659:
629:
628:
624:
582:
581:
577:
547:
546:
542:
504:
503:
499:
469:
468:
464:
420:
419:
412:
407:
399:click chemistry
366:
290:
253:
164:
155:
149:
72:tRNA synthetase
64:
17:
12:
11:
5:
1432:
1430:
1422:
1421:
1419:Human proteins
1416:
1411:
1401:
1400:
1395:
1394:
1357:Molecular Cell
1339:
1304:(2): 151–160.
1281:
1224:
1158:
1129:(2): 210–225.
1109:
1043:
975:
911:
890:(5): 257–266.
870:
841:(4): 737–747.
821:
758:
714:
657:
622:
575:
540:
513:(1): 413–444.
497:
462:
409:
408:
406:
403:
390:glycoproteins.
365:
359:
329:vasculogenesis
289:
286:
278:Alessio Ciulli
252:
249:
189:Kevan Shokat's
174:Human protein
163:
160:
154:
151:
63:
60:
42:protein–ligand
15:
13:
10:
9:
6:
4:
3:
2:
1431:
1420:
1417:
1415:
1412:
1410:
1407:
1406:
1404:
1390:
1386:
1381:
1376:
1371:
1366:
1362:
1358:
1354:
1346:
1344:
1340:
1335:
1331:
1327:
1323:
1319:
1315:
1311:
1307:
1303:
1299:
1295:
1288:
1286:
1282:
1277:
1273:
1268:
1263:
1259:
1255:
1251:
1247:
1243:
1239:
1235:
1228:
1225:
1220:
1216:
1211:
1206:
1202:
1198:
1194:
1190:
1186:
1182:
1178:
1174:
1170:
1162:
1159:
1154:
1150:
1145:
1140:
1136:
1132:
1128:
1124:
1120:
1113:
1110:
1105:
1101:
1096:
1091:
1087:
1083:
1079:
1075:
1071:
1067:
1063:
1059:
1055:
1047:
1044:
1039:
1035:
1030:
1025:
1021:
1017:
1013:
1009:
1005:
1001:
997:
993:
989:
982:
980:
976:
971:
967:
963:
959:
955:
951:
947:
943:
939:
935:
931:
927:
923:
915:
912:
907:
903:
898:
893:
889:
885:
881:
874:
871:
866:
862:
857:
852:
848:
844:
840:
836:
832:
825:
822:
817:
813:
809:
805:
801:
797:
793:
789:
785:
781:
777:
773:
769:
762:
759:
754:
750:
745:
740:
737:(2): 91–101.
736:
732:
728:
721:
719:
715:
710:
706:
701:
696:
692:
688:
684:
680:
676:
672:
668:
661:
658:
653:
649:
645:
641:
637:
633:
626:
623:
618:
614:
610:
606:
602:
598:
594:
590:
586:
579:
576:
571:
567:
563:
559:
555:
551:
544:
541:
536:
532:
528:
524:
520:
516:
512:
508:
501:
498:
493:
489:
485:
481:
478:(1): 99–124.
477:
473:
466:
463:
458:
454:
449:
444:
440:
436:
432:
428:
424:
417:
415:
411:
404:
402:
400:
396:
391:
387:
383:
379:
370:
363:
360:
358:
356:
352:
347:
342:
338:
334:
330:
326:
322:
318:
317:galactosidase
314:
310:
306:
302:
294:
287:
285:
284:
279:
274:
270:
266:
257:
250:
248:
246:
242:
238:
234:
230:
226:
221:
219:
215:
211:
205:
203:
199:
195:
190:
185:
184:phosphorylate
181:
177:
168:
161:
159:
152:
150:
147:
145:
141:
137:
133:
129:
124:
120:
116:
115:cyclosporin A
112:
103:
99:
97:
93:
89:
85:
81:
77:
73:
69:
61:
59:
56:
52:
47:
43:
38:
34:
31:is a tool in
30:
21:
1360:
1356:
1301:
1297:
1241:
1237:
1227:
1176:
1172:
1161:
1126:
1122:
1112:
1061:
1057:
1046:
995:
991:
929:
925:
914:
887:
883:
873:
838:
834:
824:
775:
771:
761:
734:
730:
674:
670:
660:
635:
631:
625:
592:
588:
578:
553:
549:
543:
510:
506:
500:
475:
471:
465:
430:
426:
377:
375:
361:
325:angiogenesis
321:nitric oxide
309:glycosylated
301:Glycosidases
299:
288:Glycosidases
262:
251:BET proteins
240:
232:
228:
224:
222:
206:
173:
156:
153:Applications
148:
108:
95:
83:
75:
65:
28:
26:
1123:Cancer Cell
341:methylation
204:, and JNK.
128:calcineurin
119:cyclophilin
80:translation
1403:Categories
405:References
353:and mouse
269:acetylated
227:-butyl-3-(
130:-mediated
1318:1552-4450
1258:2041-6520
1201:0028-0836
1086:0028-0836
1020:0036-8075
954:0028-0836
800:0028-0836
691:0002-7863
652:0002-7863
609:0968-0896
570:0570-0833
527:0066-4154
273:histones.
200:, Pho85,
1409:Genetics
1389:32325029
1334:58561892
1326:30598545
1276:29732121
1219:20871596
1153:24525235
1104:20871596
1038:25323695
962:11014197
865:23953109
808:14574415
709:28294608
535:20307192
457:30078633
357:models.
351:ischemia
333:pro-drug
51:cofactor
1380:7276986
1267:5909127
1210:3010259
1181:Bibcode
1144:4004960
1095:3010259
1066:Bibcode
1029:4458378
1000:Bibcode
992:Science
970:4430890
934:Bibcode
906:9501066
856:3950538
816:4391711
780:Bibcode
753:9495830
700:5385525
617:9784856
492:1942071
448:6195450
337:NONOate
210:kinetin
176:kinases
162:Kinases
136:T cells
68:E. coli
62:History
37:isoform
1387:
1377:
1332:
1324:
1316:
1274:
1264:
1256:
1217:
1207:
1199:
1173:Nature
1151:
1141:
1102:
1092:
1084:
1058:Nature
1036:
1026:
1018:
968:
960:
952:
926:Nature
904:
863:
853:
814:
806:
798:
772:Nature
751:
707:
697:
689:
650:
615:
607:
568:
533:
525:
490:
455:
445:
46:steric
1330:S2CID
966:S2CID
812:S2CID
214:PINK1
208:with
1385:PMID
1322:PMID
1314:ISSN
1272:PMID
1254:ISSN
1215:PMID
1197:ISSN
1149:PMID
1100:PMID
1082:ISSN
1034:PMID
1016:ISSN
958:PMID
950:ISSN
902:PMID
861:PMID
835:Cell
804:PMID
796:ISSN
749:PMID
705:PMID
687:ISSN
648:ISSN
613:PMID
605:ISSN
566:ISSN
531:PMID
523:ISSN
488:PMID
453:PMID
376:The
327:and
263:The
245:IC50
225:tert
202:ERK2
198:CDK1
178:use
90:and
27:The
1375:PMC
1365:doi
1306:doi
1262:PMC
1246:doi
1205:PMC
1189:doi
1177:468
1139:PMC
1131:doi
1090:PMC
1074:doi
1062:468
1024:PMC
1008:doi
996:346
942:doi
930:407
892:doi
851:PMC
843:doi
839:154
788:doi
776:425
739:doi
695:PMC
679:doi
675:139
640:doi
636:119
597:doi
558:doi
515:doi
480:doi
476:222
443:PMC
435:doi
395:UDP
265:BET
180:ATP
1405::
1383:.
1373:.
1361:78
1359:.
1355:.
1342:^
1328:.
1320:.
1312:.
1302:15
1300:.
1296:.
1284:^
1270:.
1260:.
1252:.
1240:.
1236:.
1213:.
1203:.
1195:.
1187:.
1175:.
1171:.
1147:.
1137:.
1127:25
1125:.
1121:.
1098:.
1088:.
1080:.
1072:.
1060:.
1056:.
1032:.
1022:.
1014:.
1006:.
994:.
990:.
978:^
964:.
956:.
948:.
940:.
928:.
924:.
900:.
886:.
882:.
859:.
849:.
837:.
833:.
810:.
802:.
794:.
786:.
774:.
770:.
747:.
733:.
729:.
717:^
703:.
693:.
685:.
673:.
669:.
646:.
634:.
611:.
603:.
591:.
587:.
564:.
554:34
552:.
529:.
521:.
511:79
509:.
486:.
474:.
451:.
441:.
431:25
429:.
425:.
413:^
378:N-
146:.
1391:.
1367::
1336:.
1308::
1278:.
1248::
1242:9
1221:.
1191::
1183::
1155:.
1133::
1106:.
1076::
1068::
1040:.
1010::
1002::
972:.
944::
936::
908:.
894::
888:8
867:.
845::
818:.
790::
782::
755:.
741::
735:5
711:.
681::
654:.
642::
619:.
599::
593:6
572:.
560::
537:.
517::
494:.
482::
459:.
437::
362:N
241:p
233:p
229:p
96:p
84:p
76:p
Text is available under the Creative Commons Attribution-ShareAlike License. Additional terms may apply.