Target Binding Site Detail
| Target General Information | Top | ||||
|---|---|---|---|---|---|
| Target ID | T65889 | Target Info | |||
| Target Name | Pyruvate kinase M2 (PKM) | ||||
| Synonyms | p58; Tumor M2-PK; Thyroid hormone-binding protein 1; THBP1; Pyruvate kinase muscle isozyme; Pyruvate kinase isozymes M1/M2; Pyruvate kinase PKM; Pyruvate kinase 2/3; PKM2; PK3; PK2; Opa-interacting protein 3; OIP3; OIP-3; Cytosolic thyroid hormone-binding protein; CTHBP | ||||
| Target Type | Clinical trial Target | ||||
| Gene Name | PKM | ||||
| Biochemical Class | Kinase | ||||
| UniProt ID | |||||
| Ligand General Information | Top | ||||
|---|---|---|---|---|---|
| Ligand Name | L-serine | Ligand Info | |||
| Canonical SMILES | C(C(C(=O)O)N)O | ||||
| InChI | 1S/C3H7NO3/c4-2(1-5)3(6)7/h2,5H,1,4H2,(H,6,7)/t2-/m0/s1 | ||||
| InChIKey | MTCFGRXMJLQNBG-REOHCLBHSA-N | ||||
| PubChem Compound ID | 5951 | ||||
| Drug Binding Sites of Target | Top | |||||
|---|---|---|---|---|---|---|
| PDB ID: 4YJ5 Crystal structure of PKM2 mutant | ||||||
| Method | X-ray diffraction | Resolution | 2.41 Å | Mutation | Yes | [1] |
| PDB Sequence |
QTQQLHAAMA
23 DTFLEHMCRL33 DIDSPPITAR43 NTGIICTIGP53 ASRSVETLKE63 MIKSGMNVAR 73 LNFSHGTHEY83 HAETIKNVRT93 ATESFASDPI103 LYRPVAVALD113 TKGPEIRTGL 123 IKGSGTAEVE133 LKKGATLKIT143 LDNAYMEKCD153 ENILWLDYKN163 ICKVVEVGSK 173 IYVDDGLISL183 QVKQKGADFL193 VTEVENGGSL203 GSKKGVNLPG213 AAVDLPAVSE 223 KDIQDLKFGV233 EQDVDMVFAS243 FIRKASDVHE253 VRKVLGEKGK263 NIKIISKIEN 273 HEGVRRFDEI283 LEASDGIMVA293 RGDLGIEIPA303 EKVFLAQKMM313 IGRCNRAGKP 323 VICATQMLES333 MIKKPRPTRA343 EGSDVANAVL353 DGADCIMLSG363 ETAKGDYPLE 373 AVRMQHLIAR383 EAEAAIYYLQ393 LFEELRRLAP403 ITSDPTEATA413 VGAVEASFKC 423 CSGAIIVLTK433 SGRSAHQVAR443 YRPRAPIIAV453 TRNPQTARQA463 HLYRGIFPVL 473 CKDPVQEAWA483 EDVDLRVNFA493 MNVGKARGFF503 KKGDVVIVLT513 GWRPGSGFTN 523 TMRVVPVP
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| PDB ID: 4B2D human PKM2 with L-serine and FBP bound. | ||||||
| Method | X-ray diffraction | Resolution | 2.30 Å | Mutation | No | [2] |
| PDB Sequence |
> Chain A
QTQQLHAAMA 23 DTFLEHMCRL33 DIDSPPITAR43 NTGIICTIGP53 ASRSVETLKE63 MIKSGMNVAR 73 LNFSHGTHEY83 HAETIKNVRT93 ATESFASDPI103 LYRPVAVALD113 TKGPEIRTGL 123 IKGSGTAEVE133 LKKGATLKIT143 LDNAYMEKCD153 ENILWLDYKN163 ICKVVEVGSK 173 IYVDDGLISL183 QVKQKGADFL193 VTEVENGGSL203 GSKKGVNLPG213 AAVDLPAVSE 223 KDIQDLKFGV233 EQDVDMVFAS243 FIRKASDVHE253 VRKVLGEKGK263 NIKIISKIEN 273 HEGVRRFDEI283 LEASDGIMVA293 RGDLGIEIPA303 EKVFLAQKMM313 IGRCNRAGKP 323 VICATQMLES333 MIKKPRPTRA343 EGSDVANAVL353 DGADCIMLSG363 ETAKGDYPLE 373 AVRMQHLIAR383 EAEAAIYHLQ393 LFEELRRLAP403 ITSDPTEATA413 VGAVEASFKC 423 CSGAIIVLTK433 SGRSAHQVAR443 YRPRAPIIAV453 TRNPQTARQA463 HLYRGIFPVL 473 CKDPVQEAWA483 EDVDLRVNFA493 MNVGKARGFF503 KKGDVVIVLT513 GWRPGSGFTN 523 TMRVVPVP> Chain D QTQQLHAAMA 23 DTFLEHMCRL33 DIDSPPITAR43 NTGIICTIGP53 ASRSVETLKE63 MIKSGMNVAR 73 LNFSHGTHEY83 HAETIKNVRT93 ATESFASDPI103 LYRPVAVALD113 TKGPEIRTGL 123 IKGSGTAEVE133 LKKGATLKLT143 LDNAYMEKCD153 ENILWLDYKN163 ICKVVEVGSK 173 IYVDDGLISL183 QVKQKGADFL193 VTEVENGGSL203 GSKKGVNLPG213 AAVDLPAVSE 223 KDIQDLKFGV233 EQDVDMVFAS243 FIRKASDVHE253 VRKVLGEKGK263 NIKIISKIEN 273 HEGVRRFDEI283 LEASDGIMVA293 RGDLGIEIPA303 EKVFLAQKMM313 IGRCNRAGKP 323 VICATQMLES333 MIKKPRPTRA343 EGSDVANAVL353 DGADCIMLSG363 ETAKGDYPLE 373 AVRMQHLIAR383 EAEAAIYHLQ393 LFEELRRLAP403 ITSDPTEATA413 VGAVEASFKC 423 CSGAIIVLTK433 SGRSAHQVAR443 YRPRAPIIAV453 TRNPQTARQA463 HLYRGIFPVL 473 CKDPVQEAWA483 EDVDLRVNFA493 MNVGKARGFF503 KKGDVVIVLT513 GWRPGSGFTN 523 TMRVVPVP
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ARG43[A]
2.355
ASN44[A]
2.703
THR45[A]
3.931
GLY46[A]
3.923
ILE47[A]
4.762
GLY68[A]
4.979
ASN70[A]
2.541
ARG106[A]
2.822
ALA463[A]
4.842
HIS464[A]
2.510
TYR466[A]
4.167
GLY468[A]
3.296
ILE469[A]
2.345
PHE470[A]
3.195
PRO471[A]
3.304
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| PDB ID: 6NUB Pyruvate Kinase M2 Mutant - S437Y in Complex with L-serine | ||||||
| Method | X-ray diffraction | Resolution | 1.70 Å | Mutation | Yes | [3] |
| PDB Sequence |
EAGTAFIQTQ
16 QLHAAMADTF26 LEHMCRLDID36 SPPITARNTG46 IICTIGPASR56 SVETLKEMIK 66 SGMNVARLNF76 SHGTHEYHAE86 TIKNVRTATE96 SFASDPILYR106 PVAVALDTKG 116 PEIRTGLIKG126 SGTAEVELKK136 GATLKITLDN146 AYMEKCDENI156 LWLDYKNICK 166 VVEVGSKIYV176 DDGLISLQVK186 QKGADFLVTE196 VENGGSLGSK206 KGVNLPGAAV 216 DLPAVSEKDI226 QDLKFGVEQD236 VDMVFASFIR246 KASDVHEVRK256 VLGEKGKNIK 266 IISKIENHEG276 VRRFDEILEA286 SDGIMVARGD296 LGIEIPAEKV306 FLAQKMMIGR 316 CNRAGKPVIC326 ATQMLESMIK336 KPRPTRAEGS346 DVANAVLDGA356 DCIMLSGETA 366 KGDYPLEAVR376 MQHLIAREAE386 AAIYHLQLFE396 ELRRLAPITS406 DPTEATAVGA 416 VEASFKCCSG426 AIIVLTKSGR436 YAHQVARYRP446 RAPIIAVTRN456 PQTARQAHLY 466 RGIFPVLCKD476 PVQEAWAEDV486 DLRVNFAMNV496 GKARGFFKKG506 DVVIVLTGWR 516 PFTNTMRVVP529 VP
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| PDB ID: 5X0I Crystal structure of PKM2 R399E mutant complexed with FBP and serine | ||||||
| Method | X-ray diffraction | Resolution | 2.64 Å | Mutation | Yes | [4] |
| PDB Sequence |
QTQQLHAAMA
23 DTFLEHMCRL33 DIDSPPITAR43 NTGIICTIGP53 ASRSVETLKE63 MIKSGMNVAR 73 LNFSHGTHEY83 HAETIKNVRT93 ATESFASDPI103 LYRPVAVALD113 TKGPEIRTGL 123 IKGSGTAEVE133 LKKGATLKIT143 LDNAYMEKCD153 ENILWLDYKN163 ICKVVEVGSK 173 IYVDDGLISL183 QVKQKGADFL193 VTEVENGGSL203 GSKKGVNLPG213 AAVDLPAVSE 223 KDIQDLKFGV233 EQDVDMVFAS243 FIRKASDVHE253 VRKVLGEKGK263 NIKIISKIEN 273 HEGVRRFDEI283 LEASDGIMVA293 RGDLGIEIPA303 EKVFLAQKMM313 IGRCNRAGKP 323 VICATQMLES333 MIKKPRPTRA343 EGSDVANAVL353 DGADCIMLSG363 ETAKGDYPLE 373 AVRMQHLIAR383 EAEAAIYHLQ393 LFEELERLAP403 ITSDPTEATA413 VGAVEASFKC 423 CSGAIIVLTK433 SGRSAHQVAR443 YRPRAPIIAV453 TRNPQTARQA463 HLYRGIFPVL 473 CKDPVQEAWA483 EDVDLRVNFA493 MNVGKARGFF503 KKGDVVIVLT513 GWRPGSGFTN 523 TMRVVPVP
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Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .SER or .SER2 or .SER3 or :3SER;style chemicals stick;color identity;select .A:43 or .A:44 or .A:45 or .A:46 or .A:70 or .A:106 or .A:463 or .A:464 or .A:466 or .A:468 or .A:469 or .A:470 or .A:471; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
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| PDB ID: 6GG6 Crystal structure of M2 PYK in complex with Serine. | ||||||
| Method | X-ray diffraction | Resolution | 2.96 Å | Mutation | No | [5] |
| PDB Sequence |
MADTFLEHMC
31 RLDIDSPPIT41 ARNTGIICTI51 GPASRSVETL61 KEMIKSGMNV71 ARLNFSHGTH 81 EYHAETIKNV91 RTATESFASD101 PILYRPVAVA111 LDTKGPEIRT121 GLIKGSGTAE 131 VELKKGATLK141 ITLDNAYMEK151 CDENILWLDY161 KNICKVVEVG171 SKIYVDDGLI 181 SLQVKQKGAD191 FLVTEVENGG201 SLGSKKGVNL211 PGAAVDLPAV221 SEKDIQDLKF 231 GVEQDVDMVF241 ASFIRKASDV251 HEVRKVLGEK261 GKNIKIISKI271 ENHEGVRRFD 281 EILEASDGIM291 VARGDLGIEI301 PAEKVFLAQK311 MMIGRCNRAG321 KPVICATQML 331 ESMIKKPRPT341 RAEGSDVANA351 VLDGADCIML361 SGETAKGDYP371 LEAVRMQHLI 381 AREAEAAIYH391 LQLFEELRRL401 APITSDPTEA411 TAVGAVEASF421 KCCSGAIIVL 431 TKSGRSAHQV441 ARYRPRAPII451 AVTRNPQTAR461 QAHLYRGIFP471 VLKDPVQEAW 482 AEDVDLRVNF492 AMNVGKARGF502 FKKGDVVIVL512 TGWRPGSGFT522 NTMRVVPVP |
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Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .SER or .SER2 or .SER3 or :3SER;style chemicals stick;color identity;select .A:43 or .A:44 or .A:45 or .A:46 or .A:70 or .A:106 or .A:463 or .A:464 or .A:466 or .A:468 or .A:469 or .A:470 or .A:471; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
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| PDB ID: 6JFB Crystal structure of human pyruvate kinase M2 isoform | ||||||
| Method | X-ray diffraction | Resolution | 2.12 Å | Mutation | No | [6] |
| PDB Sequence |
EAGTAFIQTQ
16 QLHAAMADTF26 LEHMCRLDID36 SPPITARNTG46 IICTIGPASR56 SVETLKEMIK 66 SGMNVARLNF76 SHGTHEYHAE86 TIKNVRTATE96 SFASDPILYR106 PVAVALDTKG 116 PEIRTGLIKG126 AEVELKKGAT139 LKITLDNAYM149 EKCDENILWL159 DYKNICKVVE 169 VGSKIYVDDG179 LISLQVKQKG189 ADFLVTEVEN199 GGSLGSKKGV209 NLPGAAVDLP 219 AVSEKDIQDL229 KFGVEQDVDM239 VFASFIRKAS249 DVHEVRKVLG259 EKGKNIKIIS 269 KIENHEGVRR279 FDEILEASDG289 IMVARGDLGI299 EIPAEKVFLA309 QKMMIGRCNR 319 AGKPVICATQ329 MLESMIKKPR339 PTRAEGSDVA349 NAVLDGADCI359 MLSGETAKGD 369 YPLEAVRMQH379 LIAREAEAAI389 YHLQLFEELR399 RLAPITSDPT409 EATAVGAVEA 419 SFKCCSGAII429 VLTKSGRSAH439 QVARYRPRAP449 IIAVTRNPQT459 ARQAHLYRGI 469 FPVLCKDPVQ479 EAWAEDVDLR489 VNFAMNVGKA499 RGFFKKGDVV509 IVLTGWRPGS 519 GFTNTMRVVP529 VP
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Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .SER or .SER2 or .SER3 or :3SER;style chemicals stick;color identity;select .A:14 or .A:43 or .A:44 or .A:45 or .A:46 or .A:70 or .A:464 or .A:466 or .A:468 or .A:469 or .A:470 or .A:471 or .A:500; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
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| References | Top | ||||
|---|---|---|---|---|---|
| REF 1 | Mutations in the PKM2 exon-10 region are associated with reduced allostery and increased nuclear translocation. doi:10.1038/s42003-019-0343-4. | ||||
| REF 2 | Serine is a natural ligand and allosteric activator of pyruvate kinase M2. Nature. 2012 Nov 15;491(7424):458-462. | ||||
| REF 3 | Mechanistic and Structural Insights into Cysteine-Mediated Inhibition of Pyruvate Kinase Muscle Isoform 2. Biochemistry. 2019 Sep 3;58(35):3669-3682. | ||||
| REF 4 | Mutations in the PKM2 exon-10 region are associated with reduced allostery and increased nuclear translocation. Commun Biol. 2019 Mar 15;2:105. | ||||
| REF 5 | An allostatic mechanism for M2 pyruvate kinase as an amino-acid sensor. Biochem J. 2018 May 31;475(10):1821-1837. | ||||
| REF 6 | Crystal structure of human pyruvate kinase M2 isoform | ||||
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