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==Crystal Structure of EGFR(L858R/T790M/C797S) in complex with Osimertinib==
==Crystal Structure of EGFR(L858R/T790M/C797S) in complex with Osimertinib==
<StructureSection load='6lud' size='340' side='right'caption='[[6lud]]' scene=''>
<StructureSection load='6lud' size='340' side='right'caption='[[6lud]], [[Resolution|resolution]] 2.05&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6LUD OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6LUD FirstGlance]. <br>
<table><tr><td colspan='2'>[[6lud]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6LUD OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6LUD FirstGlance]. <br>
</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6lud FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6lud OCA], [http://pdbe.org/6lud PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6lud RCSB], [http://www.ebi.ac.uk/pdbsum/6lud PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6lud ProSAT]</span></td></tr>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=YY3:N-(2-{[2-(DIMETHYLAMINO)ETHYL](METHYL)AMINO}-4-METHOXY-5-{[4-(1-METHYL-1H-INDOL-3-YL)PYRIMIDIN-2-YL]AMINO}PHENYL)PROP-2-ENAMIDE'>YY3</scene></td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">EGFR, ERBB, ERBB1, HER1 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Receptor_protein-tyrosine_kinase Receptor protein-tyrosine kinase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.1 2.7.10.1] </span></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6lud FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6lud OCA], [https://pdbe.org/6lud PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6lud RCSB], [https://www.ebi.ac.uk/pdbsum/6lud PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6lud ProSAT]</span></td></tr>
</table>
</table>
== Disease ==
[[https://www.uniprot.org/uniprot/EGFR_HUMAN EGFR_HUMAN]] Defects in EGFR are associated with lung cancer (LNCR) [MIM:[https://omim.org/entry/211980 211980]]. LNCR is a common malignancy affecting tissues of the lung. The most common form of lung cancer is non-small cell lung cancer (NSCLC) that can be divided into 3 major histologic subtypes: squamous cell carcinoma, adenocarcinoma, and large cell lung cancer. NSCLC is often diagnosed at an advanced stage and has a poor prognosis.
== Function ==
[[https://www.uniprot.org/uniprot/EGFR_HUMAN EGFR_HUMAN]] Receptor tyrosine kinase binding ligands of the EGF family and activating several signaling cascades to convert extracellular cues into appropriate cellular responses. Known ligands include EGF, TGFA/TGF-alpha, amphiregulin, epigen/EPGN, BTC/betacellulin, epiregulin/EREG and HBEGF/heparin-binding EGF. Ligand binding triggers receptor homo- and/or heterodimerization and autophosphorylation on key cytoplasmic residues. The phosphorylated receptor recruits adapter proteins like GRB2 which in turn activates complex downstream signaling cascades. Activates at least 4 major downstream signaling cascades including the RAS-RAF-MEK-ERK, PI3 kinase-AKT, PLCgamma-PKC and STATs modules. May also activate the NF-kappa-B signaling cascade. Also directly phosphorylates other proteins like RGS16, activating its GTPase activity and probably coupling the EGF receptor signaling to the G protein-coupled receptor signaling. Also phosphorylates MUC1 and increases its interaction with SRC and CTNNB1/beta-catenin.<ref>PMID:7657591</ref> <ref>PMID:11602604</ref> <ref>PMID:12873986</ref> <ref>PMID:10805725</ref> <ref>PMID:11116146</ref> <ref>PMID:11483589</ref> <ref>PMID:17115032</ref> <ref>PMID:21258366</ref> <ref>PMID:12297050</ref> <ref>PMID:12620237</ref> <ref>PMID:15374980</ref> <ref>PMID:19560417</ref> <ref>PMID:20837704</ref>  Isoform 2 may act as an antagonist of EGF action.<ref>PMID:7657591</ref> <ref>PMID:11602604</ref> <ref>PMID:12873986</ref> <ref>PMID:10805725</ref> <ref>PMID:11116146</ref> <ref>PMID:11483589</ref> <ref>PMID:17115032</ref> <ref>PMID:21258366</ref> <ref>PMID:12297050</ref> <ref>PMID:12620237</ref> <ref>PMID:15374980</ref> <ref>PMID:19560417</ref> <ref>PMID:20837704</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Osimertinib is the only EGFR-tyrosine kinase inhibitor (TKI) capable of overcoming EGFR-T790M-mutated NSCLC, but osimertinib-resistant EGFR triple mutations (Del19/T790M/C797S or L858R/T790M/C797S) have been reported. Although allosteric EGFR TKIs (eg. EAI-045) which potentially overcome L858R/T790M/C797S have been identified, there are no effective inhibitors against Del19/T790M/C797S. In this study, we identified CH7233163 as having the potential to overcome EGFR-Del19/T790M/C797S. CH7233163 showed potent antitumor activities against tumor with EGFR-Del19/T790M/C797S in vitro and in vivo. In addition to EGFR-Del19/T790M/C797S, the characterization assays showed that CH7233163 more selectively inhibits various types of EGFR mutants (eg. L858R/T790M/C797S, L858R/T790M, Del19/T790M, Del19 and L858R) over wild-type (WT). Furthermore, crystal structure analysis suggested that CH7233163 is a non-covalent ATP competitive inhibitor for EGFR-Del19/T790M/C797S that utilizes multiple interactions with the EGFR's alphaC-helix-in conformation to achieve potent inhibitory activity and mutant selectivity. Therefore, we conclude that CH7233163 is a potentially effective therapy for osimertinib resistant patients, especially in cases of EGFR-Del19/T790M/C797S.
CH7233163 overcomes osimertinib resistant EGFR-Del19/T790M/C797S mutation.,Kashima K, Kawauchi H, Tanimura H, Tachibana Y, Chiba T, Torizawa T, Sakamoto H Mol Cancer Ther. 2020 Sep 17. pii: 1535-7163.MCT-20-0229. doi:, 10.1158/1535-7163.MCT-20-0229. PMID:32943545<ref>PMID:32943545</ref>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6lud" style="background-color:#fffaf0;"></div>
==See Also==
*[[Epidermal growth factor receptor 3D structures|Epidermal growth factor receptor 3D structures]]
== References ==
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Human]]
[[Category: Large Structures]]
[[Category: Large Structures]]
[[Category: Chiba T]]
[[Category: Receptor protein-tyrosine kinase]]
[[Category: Endo M]]
[[Category: Chiba, T]]
[[Category: Fukami TA]]
[[Category: Endo, M]]
[[Category: Kashima K]]
[[Category: Fukami, T A]]
[[Category: Kawauchi H]]
[[Category: Kashima, K]]
[[Category: Sakamoto H]]
[[Category: Kawauchi, H]]
[[Category: Sato S]]
[[Category: Sakamoto, H]]
[[Category: Torizawa T]]
[[Category: Sato, S]]
[[Category: Torizawa, T]]
[[Category: Inhibitor]]
[[Category: Protein kinase]]
[[Category: Transferase-transferase inhibitor complex]]

Revision as of 09:23, 25 August 2021

Crystal Structure of EGFR(L858R/T790M/C797S) in complex with OsimertinibCrystal Structure of EGFR(L858R/T790M/C797S) in complex with Osimertinib

Structural highlights

6lud is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Gene:EGFR, ERBB, ERBB1, HER1 (HUMAN)
Activity:Receptor protein-tyrosine kinase, with EC number 2.7.10.1
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

[EGFR_HUMAN] Defects in EGFR are associated with lung cancer (LNCR) [MIM:211980]. LNCR is a common malignancy affecting tissues of the lung. The most common form of lung cancer is non-small cell lung cancer (NSCLC) that can be divided into 3 major histologic subtypes: squamous cell carcinoma, adenocarcinoma, and large cell lung cancer. NSCLC is often diagnosed at an advanced stage and has a poor prognosis.

Function

[EGFR_HUMAN] Receptor tyrosine kinase binding ligands of the EGF family and activating several signaling cascades to convert extracellular cues into appropriate cellular responses. Known ligands include EGF, TGFA/TGF-alpha, amphiregulin, epigen/EPGN, BTC/betacellulin, epiregulin/EREG and HBEGF/heparin-binding EGF. Ligand binding triggers receptor homo- and/or heterodimerization and autophosphorylation on key cytoplasmic residues. The phosphorylated receptor recruits adapter proteins like GRB2 which in turn activates complex downstream signaling cascades. Activates at least 4 major downstream signaling cascades including the RAS-RAF-MEK-ERK, PI3 kinase-AKT, PLCgamma-PKC and STATs modules. May also activate the NF-kappa-B signaling cascade. Also directly phosphorylates other proteins like RGS16, activating its GTPase activity and probably coupling the EGF receptor signaling to the G protein-coupled receptor signaling. Also phosphorylates MUC1 and increases its interaction with SRC and CTNNB1/beta-catenin.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] Isoform 2 may act as an antagonist of EGF action.[14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26]

Publication Abstract from PubMed

Osimertinib is the only EGFR-tyrosine kinase inhibitor (TKI) capable of overcoming EGFR-T790M-mutated NSCLC, but osimertinib-resistant EGFR triple mutations (Del19/T790M/C797S or L858R/T790M/C797S) have been reported. Although allosteric EGFR TKIs (eg. EAI-045) which potentially overcome L858R/T790M/C797S have been identified, there are no effective inhibitors against Del19/T790M/C797S. In this study, we identified CH7233163 as having the potential to overcome EGFR-Del19/T790M/C797S. CH7233163 showed potent antitumor activities against tumor with EGFR-Del19/T790M/C797S in vitro and in vivo. In addition to EGFR-Del19/T790M/C797S, the characterization assays showed that CH7233163 more selectively inhibits various types of EGFR mutants (eg. L858R/T790M/C797S, L858R/T790M, Del19/T790M, Del19 and L858R) over wild-type (WT). Furthermore, crystal structure analysis suggested that CH7233163 is a non-covalent ATP competitive inhibitor for EGFR-Del19/T790M/C797S that utilizes multiple interactions with the EGFR's alphaC-helix-in conformation to achieve potent inhibitory activity and mutant selectivity. Therefore, we conclude that CH7233163 is a potentially effective therapy for osimertinib resistant patients, especially in cases of EGFR-Del19/T790M/C797S.

CH7233163 overcomes osimertinib resistant EGFR-Del19/T790M/C797S mutation.,Kashima K, Kawauchi H, Tanimura H, Tachibana Y, Chiba T, Torizawa T, Sakamoto H Mol Cancer Ther. 2020 Sep 17. pii: 1535-7163.MCT-20-0229. doi:, 10.1158/1535-7163.MCT-20-0229. PMID:32943545[27]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

See Also

References

  1. ↑ Galisteo ML, Dikic I, Batzer AG, Langdon WY, Schlessinger J. Tyrosine phosphorylation of the c-cbl proto-oncogene protein product and association with epidermal growth factor (EGF) receptor upon EGF stimulation. J Biol Chem. 1995 Sep 1;270(35):20242-5. PMID:7657591
  2. ↑ Derrien A, Druey KM. RGS16 function is regulated by epidermal growth factor receptor-mediated tyrosine phosphorylation. J Biol Chem. 2001 Dec 21;276(51):48532-8. Epub 2001 Oct 15. PMID:11602604 doi:10.1074/jbc.M108862200
  3. ↑ Shao H, Cheng HY, Cook RG, Tweardy DJ. Identification and characterization of signal transducer and activator of transcription 3 recruitment sites within the epidermal growth factor receptor. Cancer Res. 2003 Jul 15;63(14):3923-30. PMID:12873986
  4. ↑ Arcaro A, Zvelebil MJ, Wallasch C, Ullrich A, Waterfield MD, Domin J. Class II phosphoinositide 3-kinases are downstream targets of activated polypeptide growth factor receptors. Mol Cell Biol. 2000 Jun;20(11):3817-30. PMID:10805725
  5. ↑ Habib AA, Chatterjee S, Park SK, Ratan RR, Lefebvre S, Vartanian T. The epidermal growth factor receptor engages receptor interacting protein and nuclear factor-kappa B (NF-kappa B)-inducing kinase to activate NF-kappa B. Identification of a novel receptor-tyrosine kinase signalosome. J Biol Chem. 2001 Mar 23;276(12):8865-74. Epub 2000 Dec 14. PMID:11116146 doi:10.1074/jbc.M008458200
  6. ↑ Li Y, Ren J, Yu W, Li Q, Kuwahara H, Yin L, Carraway KL 3rd, Kufe D. The epidermal growth factor receptor regulates interaction of the human DF3/MUC1 carcinoma antigen with c-Src and beta-catenin. J Biol Chem. 2001 Sep 21;276(38):35239-42. Epub 2001 Aug 1. PMID:11483589 doi:10.1074/jbc.C100359200
  7. ↑ Wang SC, Nakajima Y, Yu YL, Xia W, Chen CT, Yang CC, McIntush EW, Li LY, Hawke DH, Kobayashi R, Hung MC. Tyrosine phosphorylation controls PCNA function through protein stability. Nat Cell Biol. 2006 Dec;8(12):1359-68. Epub 2006 Nov 19. PMID:17115032 doi:10.1038/ncb1501
  8. ↑ Hsu JM, Chen CT, Chou CK, Kuo HP, Li LY, Lin CY, Lee HJ, Wang YN, Liu M, Liao HW, Shi B, Lai CC, Bedford MT, Tsai CH, Hung MC. Crosstalk between Arg 1175 methylation and Tyr 1173 phosphorylation negatively modulates EGFR-mediated ERK activation. Nat Cell Biol. 2011 Feb;13(2):174-81. doi: 10.1038/ncb2158. Epub 2011 Jan 23. PMID:21258366 doi:10.1038/ncb2158
  9. ↑ Ogiso H, Ishitani R, Nureki O, Fukai S, Yamanaka M, Kim JH, Saito K, Sakamoto A, Inoue M, Shirouzu M, Yokoyama S. Crystal structure of the complex of human epidermal growth factor and receptor extracellular domains. Cell. 2002 Sep 20;110(6):775-87. PMID:12297050
  10. ↑ Ferguson KM, Berger MB, Mendrola JM, Cho HS, Leahy DJ, Lemmon MA. EGF activates its receptor by removing interactions that autoinhibit ectodomain dimerization. Mol Cell. 2003 Feb;11(2):507-17. PMID:12620237
  11. ↑ Wood ER, Truesdale AT, McDonald OB, Yuan D, Hassell A, Dickerson SH, Ellis B, Pennisi C, Horne E, Lackey K, Alligood KJ, Rusnak DW, Gilmer TM, Shewchuk L. A unique structure for epidermal growth factor receptor bound to GW572016 (Lapatinib): relationships among protein conformation, inhibitor off-rate, and receptor activity in tumor cells. Cancer Res. 2004 Sep 15;64(18):6652-9. PMID:15374980 doi:10.1158/0008-5472.CAN-04-1168
  12. ↑ Red Brewer M, Choi SH, Alvarado D, Moravcevic K, Pozzi A, Lemmon MA, Carpenter G. The juxtamembrane region of the EGF receptor functions as an activation domain. Mol Cell. 2009 Jun 26;34(6):641-51. PMID:19560417 doi:10.1016/j.molcel.2009.04.034
  13. ↑ Lu C, Mi LZ, Grey MJ, Zhu J, Graef E, Yokoyama S, Springer TA. Structural Evidence for Loose Linkage between Ligand Binding and Kinase Activation in the Epidermal Growth Factor Receptor. Mol Cell Biol. 2010 Sep 13. PMID:20837704 doi:10.1128/MCB.00742-10
  14. ↑ Galisteo ML, Dikic I, Batzer AG, Langdon WY, Schlessinger J. Tyrosine phosphorylation of the c-cbl proto-oncogene protein product and association with epidermal growth factor (EGF) receptor upon EGF stimulation. J Biol Chem. 1995 Sep 1;270(35):20242-5. PMID:7657591
  15. ↑ Derrien A, Druey KM. RGS16 function is regulated by epidermal growth factor receptor-mediated tyrosine phosphorylation. J Biol Chem. 2001 Dec 21;276(51):48532-8. Epub 2001 Oct 15. PMID:11602604 doi:10.1074/jbc.M108862200
  16. ↑ Shao H, Cheng HY, Cook RG, Tweardy DJ. Identification and characterization of signal transducer and activator of transcription 3 recruitment sites within the epidermal growth factor receptor. Cancer Res. 2003 Jul 15;63(14):3923-30. PMID:12873986
  17. ↑ Arcaro A, Zvelebil MJ, Wallasch C, Ullrich A, Waterfield MD, Domin J. Class II phosphoinositide 3-kinases are downstream targets of activated polypeptide growth factor receptors. Mol Cell Biol. 2000 Jun;20(11):3817-30. PMID:10805725
  18. ↑ Habib AA, Chatterjee S, Park SK, Ratan RR, Lefebvre S, Vartanian T. The epidermal growth factor receptor engages receptor interacting protein and nuclear factor-kappa B (NF-kappa B)-inducing kinase to activate NF-kappa B. Identification of a novel receptor-tyrosine kinase signalosome. J Biol Chem. 2001 Mar 23;276(12):8865-74. Epub 2000 Dec 14. PMID:11116146 doi:10.1074/jbc.M008458200
  19. ↑ Li Y, Ren J, Yu W, Li Q, Kuwahara H, Yin L, Carraway KL 3rd, Kufe D. The epidermal growth factor receptor regulates interaction of the human DF3/MUC1 carcinoma antigen with c-Src and beta-catenin. J Biol Chem. 2001 Sep 21;276(38):35239-42. Epub 2001 Aug 1. PMID:11483589 doi:10.1074/jbc.C100359200
  20. ↑ Wang SC, Nakajima Y, Yu YL, Xia W, Chen CT, Yang CC, McIntush EW, Li LY, Hawke DH, Kobayashi R, Hung MC. Tyrosine phosphorylation controls PCNA function through protein stability. Nat Cell Biol. 2006 Dec;8(12):1359-68. Epub 2006 Nov 19. PMID:17115032 doi:10.1038/ncb1501
  21. ↑ Hsu JM, Chen CT, Chou CK, Kuo HP, Li LY, Lin CY, Lee HJ, Wang YN, Liu M, Liao HW, Shi B, Lai CC, Bedford MT, Tsai CH, Hung MC. Crosstalk between Arg 1175 methylation and Tyr 1173 phosphorylation negatively modulates EGFR-mediated ERK activation. Nat Cell Biol. 2011 Feb;13(2):174-81. doi: 10.1038/ncb2158. Epub 2011 Jan 23. PMID:21258366 doi:10.1038/ncb2158
  22. ↑ Ogiso H, Ishitani R, Nureki O, Fukai S, Yamanaka M, Kim JH, Saito K, Sakamoto A, Inoue M, Shirouzu M, Yokoyama S. Crystal structure of the complex of human epidermal growth factor and receptor extracellular domains. Cell. 2002 Sep 20;110(6):775-87. PMID:12297050
  23. ↑ Ferguson KM, Berger MB, Mendrola JM, Cho HS, Leahy DJ, Lemmon MA. EGF activates its receptor by removing interactions that autoinhibit ectodomain dimerization. Mol Cell. 2003 Feb;11(2):507-17. PMID:12620237
  24. ↑ Wood ER, Truesdale AT, McDonald OB, Yuan D, Hassell A, Dickerson SH, Ellis B, Pennisi C, Horne E, Lackey K, Alligood KJ, Rusnak DW, Gilmer TM, Shewchuk L. A unique structure for epidermal growth factor receptor bound to GW572016 (Lapatinib): relationships among protein conformation, inhibitor off-rate, and receptor activity in tumor cells. Cancer Res. 2004 Sep 15;64(18):6652-9. PMID:15374980 doi:10.1158/0008-5472.CAN-04-1168
  25. ↑ Red Brewer M, Choi SH, Alvarado D, Moravcevic K, Pozzi A, Lemmon MA, Carpenter G. The juxtamembrane region of the EGF receptor functions as an activation domain. Mol Cell. 2009 Jun 26;34(6):641-51. PMID:19560417 doi:10.1016/j.molcel.2009.04.034
  26. ↑ Lu C, Mi LZ, Grey MJ, Zhu J, Graef E, Yokoyama S, Springer TA. Structural Evidence for Loose Linkage between Ligand Binding and Kinase Activation in the Epidermal Growth Factor Receptor. Mol Cell Biol. 2010 Sep 13. PMID:20837704 doi:10.1128/MCB.00742-10
  27. ↑ Kashima K, Kawauchi H, Tanimura H, Tachibana Y, Chiba T, Torizawa T, Sakamoto H. CH7233163 overcomes osimertinib resistant EGFR-Del19/T790M/C797S mutation. Mol Cancer Ther. 2020 Sep 17. pii: 1535-7163.MCT-20-0229. doi:, 10.1158/1535-7163.MCT-20-0229. PMID:32943545 doi:http://dx.doi.org/10.1158/1535-7163.MCT-20-0229

6lud, resolution 2.05Å

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