Target Binding Site Detail
| Target General Information | Top | ||||
|---|---|---|---|---|---|
| Target ID | T74977 | Target Info | |||
| Target Name | Dual specificity protein kinase TTK (MPS1) | ||||
| Synonyms | Tyrosine threonine kinase; Phosphotyrosine picked threonine-protein kinase; PYT; MPS1L1 | ||||
| Target Type | Clinical trial Target | ||||
| Gene Name | TTK | ||||
| Biochemical Class | Kinase | ||||
| UniProt ID | |||||
| Ligand General Information | Top | ||||
|---|---|---|---|---|---|
| Ligand Name | NMS-P715 | Ligand Info | |||
| Canonical SMILES | CCC1=C(C(=CC=C1)CC)NC(=O)C2=NN(C3=C2CCC4=CN=C(N=C43)NC5=C(C=C(C=C5)C(=O)NC6CCN(CC6)C)OC(F)(F)F)C | ||||
| InChI | 1S/C35H39F3N8O3/c1-5-20-8-7-9-21(6-2)28(20)42-33(48)30-25-12-10-23-19-39-34(43-29(23)31(25)46(4)44-30)41-26-13-11-22(18-27(26)49-35(36,37)38)32(47)40-24-14-16-45(3)17-15-24/h7-9,11,13,18-19,24H,5-6,10,12,14-17H2,1-4H3,(H,40,47)(H,42,48)(H,39,41,43) | ||||
| InChIKey | JFOAJUGFHDCBJJ-UHFFFAOYSA-N | ||||
| PubChem Compound ID | 44556162 | ||||
| Drug Binding Sites of Target | Top | |||||
|---|---|---|---|---|---|---|
| PDB ID: 2X9E HUMAN MPS1 IN COMPLEX WITH NMS-P715 | ||||||
| Method | X-ray diffraction | Resolution | 3.10 Å | Mutation | No | [1] |
| PDB Sequence |
NECISVKGRI
524 YSILKQIGSG534 GSSKVFQVLN544 EKKQIYAIKY554 VNLEEADNQT564 LDSYRNEIAY 574 LNKLQQHSDK584 IIRLYDYEIT594 DQYIYMVMEC604 GNIDLNSWLK614 KKKSIDPWER 624 KSYWKNMLEA634 VHTIHQHGIV644 HSDLKPANFL654 IVDGMLKLID664 FGIANGTVNY 689 MPPEAIKDMI711 SPKSDVWSLG721 CILYYMTYGK731 TPFQQIINQI741 SKLHAIIDPN 751 HEIEFPDIPE761 KDLQDVLKCC771 LKRDPKQRIS781 IPELLAHPYV791 QIQT |
|||||
|
|
LYS529
3.446
ILE531
3.376
GLY532
4.461
SER533
4.285
GLY534
3.666
SER537
3.332
LYS538
4.510
VAL539
3.760
GLN541
2.639
ILE549
4.742
ALA551
3.633
LYS553
2.972
ILE586
3.438
|
|||||
| PDB ID: 5AP7 Naturally Occurring Mutations in the MPS1 Gene Predispose Cells to Kinase Inhibitor Drug Resistance. | ||||||
| Method | X-ray diffraction | Resolution | 2.45 Å | Mutation | Yes | [2] |
| PDB Sequence |
GTENLYFQSM
518 SVKGRIYSIL528 KQIGSGGSSK538 VFQVLNEKKQ548 IYAIKYVNLE558 EADNQTLDSY 568 RNEIAYLNKL578 QQHSDKIIRL588 YDYEITDQYI598 YMVMEWGNID608 LNSWLKKKKS 618 IDPWERKSYW628 KNMLEAVHTI638 HQHGIVHSDL648 KPANFLIVDG658 MLKLIDFGIA 668 NQMQPVGTVN688 YMPPEAIKDI711 SPKSDVWSLG721 CILYYMTYGK731 TPFQQIINQI 741 SKLHAIIDPN751 HEIEFPDIPE761 KDLQDVLKCC771 LKRDPKQRIS781 IPELLAHPYV 791 QIQ
|
|||||
|
|
LYS529
3.902
ILE531
3.182
GLY532
4.538
SER533
4.381
GLY534
4.061
SER537
3.508
LYS538
4.448
VAL539
3.515
GLN541
2.855
ALA551
3.385
LYS553
2.761
ILE586
3.540
MET602
3.351
|
|||||
| PDB ID: 5NTT Crystal structure of human Mps1 (TTK) C604Y mutant in complex with NMS-P715 | ||||||
| Method | X-ray diffraction | Resolution | 2.75 Å | Mutation | Yes | [3] |
| PDB Sequence |
ENLYFQSMSV
520 KGRIYSILKQ530 IGSGGSSKVF540 QVLNEKKQIY550 AIKYVNLEEA560 DNQTLDSYRN 570 EIAYLNKLQQ580 HSDKIIRLYD590 YEITDQYIYM600 VMEYGNIDLN610 SWLKKKKSID 620 PWERKSYWKN630 MLEAVHTIHQ640 HGIVHSDLKP650 ANFLIVDGML660 KLIDFGIANQ 670 MQPDTTSVVK680 DSQVGVNYMP691 PEAIKDMSKI711 SPKSDVWSLG721 CILYYMTYGK 731 TPFQQIINQI741 SKLHAIIDPN751 HEIEFPDIPE761 KDLQDVLKCC771 LKRDPKQRIS 781 IPELLAHPYV791 QIQTHP
|
|||||
|
|
LYS529
3.370
ILE531
3.262
GLY532
4.666
SER533
3.685
GLY534
3.283
SER537
3.409
VAL539
3.817
GLN541
3.532
ALA551
3.311
LYS553
2.963
ILE586
3.744
MET602
3.493
GLU603
3.409
|
|||||
| References | Top | ||||
|---|---|---|---|---|---|
| REF 1 | Targeting the mitotic checkpoint for cancer therapy with NMS-P715, an inhibitor of MPS1 kinase. Cancer Res. 2010 Dec 15;70(24):10255-64. | ||||
| REF 2 | Naturally Occurring Mutations in the MPS1 Gene Predispose Cells to Kinase Inhibitor Drug Resistance. Cancer Res. 2015 Aug 15;75(16):3340-54. | ||||
| REF 3 | Understanding inhibitor resistance in Mps1 kinase through novel biophysical assays and structures. J Biol Chem. 2017 Sep 1;292(35):14496-14504. | ||||
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