Target Binding Site Detail
| Target General Information | Top | ||||
|---|---|---|---|---|---|
| Target ID | T13057 | Target Info | |||
| Target Name | Protein-tyrosine phosphatase SHP-2 (PTPN11) | ||||
| Synonyms | Tyrosine-protein phosphatase non-receptor type 11; SHPTP2; SHP2; SHP-2; SH-PTP3; SH-PTP2; Protein-tyrosine phosphatase SHP2; Protein-tyrosine phosphatase 2C; Protein-tyrosine phosphatase 1D; PTP2C; PTP-2C; PTP-1D | ||||
| Target Type | Clinical trial Target | ||||
| Gene Name | PTPN11 | ||||
| Biochemical Class | Phosphoric monoester hydrolase | ||||
| UniProt ID | |||||
| Ligand General Information | Top | ||||
|---|---|---|---|---|---|
| Ligand Name | 6-(4-Azanyl-4-Methyl-Piperidin-1-Yl)-3-[2,3-Bis(Chloranyl)phenyl]pyrazin-2-Amine | Ligand Info | |||
| Canonical SMILES | CC1(CCN(CC1)C2=CN=C(C(=N2)N)C3=C(C(=CC=C3)Cl)Cl)N | ||||
| InChI | 1S/C16H19Cl2N5/c1-16(20)5-7-23(8-6-16)12-9-21-14(15(19)22-12)10-3-2-4-11(17)13(10)18/h2-4,9H,5-8,20H2,1H3,(H2,19,22) | ||||
| InChIKey | YGUFCDOEKKVKJK-UHFFFAOYSA-N | ||||
| PubChem Compound ID | 118238298 | ||||
| Drug Binding Sites of Target | Top | |||||
|---|---|---|---|---|---|---|
| PDB ID: 6CMR Closed structure of active SHP2 mutant E76D bound to SHP099 inhibitor | ||||||
| Method | X-ray diffraction | Resolution | 2.21 Å | Mutation | Yes | [1] |
| PDB Sequence |
TSRRWFHPNI
11 TGVEAENLLL21 TRGVDGSFLA31 RPSKSNPGDF41 TLSVRRNGAV51 THIKIQNTGD 61 YYDLYGGEKF71 ATLADLVQYY81 MEHHGQLKED94 VIELKYPLNC104 ADPTSERWFH 114 GHLSGKEAEK124 LLTEKGKHGS134 FLVRESQSHP144 GDFVLSVRTG154 DDSNDGKSKV 167 THVMIRCQEL177 KYDVGGGERF187 DSLTDLVEHY197 KKNPMVETLG207 TVLQLKQPLN 217 TTRINAAEIE227 SRVRELSKQG246 FWEEFETLQQ256 QECKLLYSRK266 EGQRQENKNK 276 NRYKNILPFD286 HTRVVLHSDY304 INANIIMPEK324 KSYIATQGCL334 QNTVNDFWRM 344 VFQENSRVIV354 MTTKEVERGK364 SKCVKYWPDE374 YALKEYGVMR384 VRNVKESAAH 394 DYTLRELKLS404 KVGQGNTERT414 VWQYHFRTWP424 DHGVPSDPGG434 VLDFLEEVHH 444 KQESIMDAGP454 VVVHCSAGIG464 RTGTFIVIDI474 LIDIIREKGV484 DCDIDVPKTI 494 QMVRSQRSGM504 VQTEAQYRFI514 YMAVQHYIET524 LQRR
|
|||||
|
|
PRO107
4.217
THR108
2.867
SER109
3.806
GLU110
2.460
ARG111
2.639
TRP112
4.096
PHE113
2.441
HIS114
2.872
GLY115
4.735
LEU216
4.444
ASN217
3.762
THR218
2.467
|
|||||
| PDB ID: 6CMS Closed structure of active SHP2 mutant E76K bound to SHP099 inhibitor | ||||||
| Method | X-ray diffraction | Resolution | 2.68 Å | Mutation | Yes | [1] |
| PDB Sequence |
TSRRWFHPNI
11 TGVEAENLLL21 TRGVDGSFLA31 RPSPGDFTLS44 VRRNGAVTHI54 KIQNTGDYYD 64 LYGGEKFATL74 AKLVQYYMEH84 HGQLKEKNGD94 VIELKYPLNC104 ADPTSERWFH 114 GHLSGKEAEK124 LLTEKGKHGS134 FLVRESQSHP144 GDFVLSVRTG154 DDKGESNDGK 164 SKVTHVMIRC174 QELKYDVGGG184 ERFDSLTDLV194 EHYKKNPMVE204 TLGTVLQLKQ 214 PLNTTRINAA224 EIESRVRELS234 KKQGFWEEFE252 TLQQQECKLL262 YSRKEGQRQE 272 NKNKNRYKNI282 LPFDHTRVVL292 HSDYINANII310 MPEKKSYIAT330 QGCLQNTVND 340 FWRMVFQENS350 RVIVMTTKEV360 ERGKSKCVKY370 WPDEYALKEY380 GVMRVRNVKE 390 SAAHDYTLRE400 LKLSKVGQGN410 TERTVWQYHF420 RTWPDHGVPS430 DPGGVLDFLE 440 EVHHKQESIM450 DAGPVVVHCS460 AGIGRTGTFI470 VIDILIDIIR480 EKGVDCDIDV 490 PKTIQMVRSQ500 RSGMVQTEAQ510 YRFIYMAVQH520 YIETLQR
|
|||||
|
|
PRO107
4.356
THR108
2.858
SER109
4.065
GLU110
2.309
ARG111
2.454
TRP112
4.145
PHE113
2.337
HIS114
2.952
GLY115
4.584
LEU216
4.462
ASN217
3.825
THR218
2.856
|
|||||
| PDB ID: 5EHR Non-receptor Protein Tyrosine Phosphatase SHP2 in Complex with Allosteric Inhibitor SHP099 | ||||||
| Method | X-ray diffraction | Resolution | 1.70 Å | Mutation | No | [2] |
| PDB Sequence |
RRWFHPNITG
13 VEAENLLLTR23 GVDGSFLARP33 SKSNPGDFTL43 SVRRNGAVTH53 IKIQNTGDYY 63 DLYGGEKFAT73 LAELVQYYME83 HIELKYPLNC104 ADPTSERWFH114 GHLSGKEAEK 124 LLTEKGKHGS134 FLVRESGDFV148 LSVRTGDSKV167 THVMIRCQEL177 KYDVGGGERF 187 DSLTDLVEHY197 KKNPMVETLG207 TVLQLKQPLN217 TTRINAAEIE227 SRVRELSKLA 237 KQGFWEEFET253 LQQQECKLLY263 SRKEGQRQEN273 KNKNRYKNIL283 PFDHTRVVLH 293 DGDPNEPVSD303 YINANIIMPE313 FKPKKSYIAT330 QGCLQNTVND340 FWRMVFQENS 350 RVIVMTTKEV360 ERGKSKCVKY370 WPDEYALKEY380 GVMRVRNVKE390 SAAHDYTLRE 400 LKLSKVGQGN410 TERTVWQYHF420 RTWPDHGVPS430 DPGGVLDFLE440 EVHHKQESIM 450 DAGPVVVHCS460 AGIGRTGTFI470 VIDILIDIIR480 EKGVDCDIDV490 PKTIQMVRSQ 500 RSGMVQTEAQ510 YRFIYMAVQH520 YIETL
|
|||||
|
|
||||||
| PDB ID: 6BMY Non-receptor Protein Tyrosine Phosphatase SHP2 in Complex with Allosteric Inhibitors SHP099 and SHP844 | ||||||
| Method | X-ray diffraction | Resolution | 2.09 Å | Mutation | No | [3] |
| PDB Sequence |
SRRWFHPNIT
12 GVEAENLLLT22 RGVDGSFLAR32 PSNPGDFTLS44 VRRNGAVTHI54 KIQNTGDYYD 64 LYGGEKFATL74 AELVQYYMEH84 HGQLKGDVIE97 LKYPLNCADP107 TSERWFHGHL 117 EKLLTEKGKH132 GSFLVRESPG145 DFVLSVRTGS165 KVTHVMIRCQ175 ELKYDVGGGE 185 RFDSLTDLVE195 HYKKNPMVET205 LGTVLQLKQP215 LNTTRINAAE225 IESRVRELSK 235 LQGFWEEFET253 LQQQECKLLY263 SRKEGQRQEN273 KNKNRYKNIL283 PFDHTRVVLH 293 DGDPPVSDYI305 NANIIMPPKK325 SYIATQGCLQ335 NTVNDFWRMV345 FQENSRVIVM 355 TTKEVERGKS365 KCVKYWPDEY375 ALKEYGVMRV385 RNVKESAAHD395 YTLRELKLSK 405 VGQGNTERTV415 WQYHFRTWPD425 HGVPSDPGGV435 LDFLEEVHHK445 QESIMDAGPV 455 VVHCSAGIGR465 TGTFIVIDIL475 IDIIREKGVD485 CDIDVPKTIQ495 MVRSQRSGMV 505 QTEAQYRFIY515 MAVQHYIETL525
|
|||||
|
Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .5OD or .5OD2 or .5OD3 or :35OD;style chemicals stick;color identity;select .A:108 or .A:110 or .A:111 or .A:112 or .A:113 or .A:114 or .A:218 or .A:219 or .A:249 or .A:250 or .A:253 or .A:254 or .A:257 or .A:489 or .A:491 or .A:492 or .A:495 or .A:511; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
|
||||||
| PDB ID: 6BMW Non-receptor Protein Tyrosine Phosphatase SHP2 in Complex with Allosteric Inhibitors SHP099 and SHP504 | ||||||
| Method | X-ray diffraction | Resolution | 2.10 Å | Mutation | No | [3] |
| PDB Sequence |
SRRWFHPNIT
12 GVEAENLLLT22 RGVDGSFLAR32 PSKPGDFTLS44 VRRNGAVTHI54 KIQNTGDYYD 64 LYGGEKFATL74 AELVQYYMEH84 HGQLKDVIEL98 KYPLNCADPT108 SERWFHGHLE 121 AEKLLTEKGK131 HGSFLVRESP144 GDFVLSVRTG154 SKVTHVMIRC174 QELKYDVGGG 184 ERFDSLTDLV194 EHYKKNPMVE204 TLGTVLQLKQ214 PLNTTRINAA224 EIESRVRELS 234 KLQGFWEEFE252 TLQQQECKLL262 YSRKEGQRQE272 NKNKNRYKNI282 LPFDHTRVVL 292 HPVSDYINAN308 IIMPKSYIAT330 QGCLQNTVND340 FWRMVFQENS350 RVIVMTTKEV 360 ERGKSKCVKY370 WPDEYALKEY380 GVMRVRNVKE390 SAAHDYTLRE400 LKLSKVGQGN 410 TERTVWQYHF420 RTWPDHGVPS430 DPGGVLDFLE440 EVHHKQESIM450 DAGPVVVHCS 460 AGIGRTGTFI470 VIDILIDIIR480 EKGVDCDIDV490 PKTIQMVRSQ500 RSGMVQTEAQ 510 YRFIYMAVQH520 YIETL
|
|||||
|
Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .5OD or .5OD2 or .5OD3 or :35OD;style chemicals stick;color identity;select .A:107 or .A:108 or .A:109 or .A:110 or .A:111 or .A:112 or .A:113 or .A:114 or .A:218 or .A:219 or .A:249 or .A:250 or .A:253 or .A:254 or .A:257 or .A:489 or .A:491 or .A:492 or .A:495 or .A:511; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
|
PRO107
4.920
THR108
2.845
SER109
4.660
GLU110
3.004
ARG111
3.531
TRP112
4.978
PHE113
3.217
HIS114
3.533
THR218
3.678
THR219
3.462
|
|||||
| PDB ID: 6BMU Non-receptor Protein Tyrosine Phosphatase SHP2 in Complex with Allosteric Inhibitors SHP099 and SHP244 | ||||||
| Method | X-ray diffraction | Resolution | 2.12 Å | Mutation | No | [3] |
| PDB Sequence |
SRRWFHPNIT
12 GVEAENLLLT22 RGVDGSFLAR32 PSNPGDFTLS44 VRRNGAVTHI54 KIQNTGDYYD 64 LYGGEKFATL74 AELVQYYMEH84 HGQLKGDVIE97 LKYPLNCADP107 TSERWFHGHL 117 EKLLTEKGKH132 GSFLVRESPG145 DFVLSVRTGS165 KVTHVMIRCQ175 ELKYDVGGGE 185 RFDSLTDLVE195 HYKKNPMVET205 LGTVLQLKQP215 LNTTRINAAE225 IESRVRELSK 235 LQGFWEEFET253 LQQQECKLLY263 SRKEGQRQEN273 KNKNRYKNIL283 PFDHTRVVLH 293 DGDPPVSDYI305 NANIIMPPKK325 SYIATQGCLQ335 NTVNDFWRMV345 FQENSRVIVM 355 TTKEVERGKS365 KCVKYWPDEY375 ALKEYGVMRV385 RNVKESAAHD395 YTLRELKLSK 405 VGQGNTERTV415 WQYHFRTWPD425 HGVPSDPGGV435 LDFLEEVHHK445 QESIMDAGPV 455 VVHCSAGIGR465 TGTFIVIDIL475 IDIIREKGVD485 CDIDVPKTIQ495 MVRSQRSGMV 505 QTEAQYRFIY515 MAVQHYIETL525
|
|||||
|
Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .5OD or .5OD2 or .5OD3 or :35OD;style chemicals stick;color identity;select .A:107 or .A:108 or .A:109 or .A:110 or .A:111 or .A:112 or .A:113 or .A:114 or .A:218 or .A:219 or .A:249 or .A:250 or .A:253 or .A:254 or .A:257 or .A:489 or .A:491 or .A:492 or .A:495 or .A:511; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
|
PRO107
4.957
THR108
2.922
SER109
4.939
GLU110
3.198
ARG111
3.336
TRP112
4.969
PHE113
2.875
HIS114
3.625
THR218
3.558
THR219
3.394
|
|||||
| PDB ID: 6CRG Crystal Structure of Shp2 E76K GOF Mutant in complex with SHP099 | ||||||
| Method | X-ray diffraction | Resolution | 2.75 Å | Mutation | Yes | [4] |
| PDB Sequence |
RRWFHPNITG
13 VEAENLLLTR23 GVDGSFLARP33 SDFTLSVRRN48 GAVTHIKIQN58 TGDYYDLYGG 68 EKFATLAKLV78 QYYMEHVIEL98 KYPLNCADPT108 SERWFHGHLS118 GKEAEKLLTE 128 KGKHGSFLVR138 ESQSHPGDFV148 LSVRTGSNDG163 KSKVTHVMIR173 CQELKYDVGG 183 GERFDSLTDL193 VEHYKKNPMV203 ETLGTVLQLK213 QPLNTTRINA223 AEIESRVREL 233 SKQGFWEEFE252 TLQQQECKLL262 YSRKEGQRQE272 NKNKNRYKNI282 LPFDHTRVVL 292 HDGPVSDYIN306 ANIIMPKSYI328 ATQGCLQNTV338 NDFWRMVFQE348 NSRVIVMTTK 358 EVERGKSKCV368 KYWPDEYALK378 EYGVMRVRNV388 KESAAHDYTL398 RELKLSKVGQ 408 GNTERTVWQY418 HFRTWPDHGV428 PSDPGGVLDF438 LEEVHHKQES448 IMDAGPVVVH 458 CSAGIGRTGT468 FIVIDILIDI478 IREKGVDCDI488 DVPKTIQMVR498 SQRSGMVQTE 508 AQYRFIYMAV518 QHYIETL
|
|||||
|
Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .5OD or .5OD2 or .5OD3 or :35OD;style chemicals stick;color identity;select .A:107 or .A:108 or .A:110 or .A:111 or .A:113 or .A:114 or .A:218 or .A:219 or .A:249 or .A:250 or .A:253 or .A:254 or .A:257 or .A:489 or .A:491 or .A:492 or .A:495 or .A:511; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
|
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| References | Top | ||||
|---|---|---|---|---|---|
| REF 1 | Mechanism of activating mutations and allosteric drug inhibition of the phosphatase SHP2. Nat Commun. 2018 Oct 30;9(1):4507. | ||||
| REF 2 | Allosteric inhibition of SHP2 phosphatase inhibits cancers driven by receptor tyrosine kinases. Nature. 2016 Jul 7;535(7610):148-52. | ||||
| REF 3 | Dual Allosteric Inhibition of SHP2 Phosphatase. ACS Chem Biol. 2018 Mar 16;13(3):647-656. | ||||
| REF 4 | Structural reorganization of SHP2 by oncogenic mutations and implications for oncoprotein resistance to allosteric inhibition. Nat Commun. 2018 Oct 30;9(1):4508. | ||||
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