4g5p

From Proteopedia

(Difference between revisions)
Jump to: navigation, search
Current revision (10:52, 6 November 2024) (edit) (undo)
 
(5 intermediate revisions not shown.)
Line 1: Line 1:
-
[[Image:4g5p.png|left|200px]]
 
-
{{STRUCTURE_4g5p| PDB=4g5p | SCENE= }}
+
==Crystal structure of EGFR kinase T790M in complex with BIBW2992==
 +
<StructureSection load='4g5p' size='340' side='right'caption='[[4g5p]], [[Resolution|resolution]] 3.17&Aring;' scene=''>
 +
== Structural highlights ==
 +
<table><tr><td colspan='2'>[[4g5p]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4G5P OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4G5P FirstGlance]. <br>
 +
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3.17&#8491;</td></tr>
 +
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=0WN:N-{4-[(3-CHLORO-4-FLUOROPHENYL)AMINO]-7-[(3S)-TETRAHYDROFURAN-3-YLOXY]QUINAZOLIN-6-YL}-4-(DIMETHYLAMINO)BUTANAMIDE'>0WN</scene></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=4g5p FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4g5p OCA], [https://pdbe.org/4g5p PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4g5p RCSB], [https://www.ebi.ac.uk/pdbsum/4g5p PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4g5p ProSAT]</span></td></tr>
 +
</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 ==
 +
Deregulation of the ErbB receptor network is well recognized as an oncogenic driver in epithelial cancers. Several targeted drugs have been developed, including antibodies and small molecule kinase inhibitors, each of them characterized by distinct patterns of ErbB receptor interactions. Understanding the precise pharmacological properties of these compounds is important for optimal use in clinical practice. Afatinib (BIBW 2992) is an ATP-competitive anilinoquinazoline derivative harboring a reactive acrylamide group and was designed to covalently bind and irreversibly block enzymatically active ErbB receptor family members. Here we show by X-ray crystallography the covalent binding of afatinib to wild-type EGFR and by mass spectrometry the covalent interaction with EGFR, EGFRL858R/T790M, HER2 and ErbB-4. Afatinib potently inhibits the enymatic activity of ErbB-4 (EC50 = 1 nM) and the proliferation of cancer cell lines driven by multiple ErbB receptor aberrations at concentrations below 100 nM. BI 37781, a close analog of afatinib lacking the acrylamide group and thus incapable of covalent bond formation, had similar potency on cells driven by EGFR or EGFRL858R, but less or no detectable activity on cells expressing EGFRL858R/ T790M HER2 or ErbB-4. These results stress the importance of the acrylamide group and show that afatinib differs from approved ErbB targeting agents by irreversibly inhibiting the kinase activity of all ErbB family members. They provide a mechanistic rationale for the distinct pharmacological features of this compound and explain the clinical activity seen in some patients resistant to antibody or kinase inhibitor therapy due to secondary mutations or ErbB receptor 'reprogramming'.
-
===Crystal structure of EGFR kinase T790M in complex with BIBW2992===
+
Target Binding Properties and Cellular Activity of Afatinib (BIBW 2992), an Irreversible ErbB Family Blocker.,Solca F, Dahl G, Zoephel A, Bader G, Sanderson M, Klein C, Kraemer O, Himmelsbach F, Haaksma E, Adolf GR J Pharmacol Exp Ther. 2012 Aug 10. PMID:22888144<ref>PMID:22888144</ref>
-
{{ABSTRACT_PUBMED_22888144}}
+
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 +
</div>
 +
<div class="pdbe-citations 4g5p" style="background-color:#fffaf0;"></div>
-
==About this Structure==
+
==See Also==
-
[[4g5p]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4G5P OCA].
+
*[[Epidermal growth factor receptor 3D structures|Epidermal growth factor receptor 3D structures]]
-
 
+
== References ==
-
==Reference==
+
<references/>
-
<ref group="xtra">PMID:022888144</ref><references group="xtra"/>
+
__TOC__
 +
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
-
[[Category: Receptor protein-tyrosine kinase]]
+
[[Category: Large Structures]]
-
[[Category: Adolf, G R.]]
+
[[Category: Adolf GR]]
-
[[Category: Bader, G.]]
+
[[Category: Bader G]]
-
[[Category: Dahl, G.]]
+
[[Category: Dahl G]]
-
[[Category: Haaksma, E.]]
+
[[Category: Haaksma E]]
-
[[Category: Himmelsbach, F.]]
+
[[Category: Himmelsbach F]]
-
[[Category: Klein, C.]]
+
[[Category: Klein C]]
-
[[Category: Kraemer, O.]]
+
[[Category: Kraemer O]]
-
[[Category: Sanderson, M.]]
+
[[Category: Sanderson M]]
-
[[Category: Solca, F.]]
+
[[Category: Solca F]]
-
[[Category: Zoephel, A.]]
+
[[Category: Zoephel A]]
-
[[Category: Egf receptor kinase mutant t790m]]
+
-
[[Category: Transferase-transferase inhibitor complex]]
+

Current revision

Crystal structure of EGFR kinase T790M in complex with BIBW2992

PDB ID 4g5p

Drag the structure with the mouse to rotate

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/4g5p"
Personal tools