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| | <StructureSection load='6op9' size='340' side='right'caption='[[6op9]], [[Resolution|resolution]] 2.50Å' scene=''> | | <StructureSection load='6op9' size='340' side='right'caption='[[6op9]], [[Resolution|resolution]] 2.50Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6op9]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. This structure supersedes the now removed PDB entry [http://oca.weizmann.ac.il/oca-bin/send-pdb?obs=1&id=4otw 4otw]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6OP9 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6OP9 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6op9]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. This structure supersedes the now removed PDB entry [http://oca.weizmann.ac.il/oca-bin/send-pdb?obs=1&id=4otw 4otw]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6OP9 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6OP9 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DB8:4-[(2,4-DICHLORO-5-METHOXYPHENYL)AMINO]-6-METHOXY-7-[3-(4-METHYLPIPERAZIN-1-YL)PROPOXY]QUINOLINE-3-CARBONITRILE'>DB8</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.501Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">ERBB3, HER3 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DB8:4-[(2,4-DICHLORO-5-METHOXYPHENYL)AMINO]-6-METHOXY-7-[3-(4-METHYLPIPERAZIN-1-YL)PROPOXY]QUINOLINE-3-CARBONITRILE'>DB8</scene></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=6op9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6op9 OCA], [https://pdbe.org/6op9 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6op9 RCSB], [https://www.ebi.ac.uk/pdbsum/6op9 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6op9 ProSAT]</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=6op9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6op9 OCA], [https://pdbe.org/6op9 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6op9 RCSB], [https://www.ebi.ac.uk/pdbsum/6op9 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6op9 ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[https://www.uniprot.org/uniprot/ERBB3_HUMAN ERBB3_HUMAN]] Defects in ERBB3 are the cause of lethal congenital contracture syndrome type 2 (LCCS2) [MIM:[https://omim.org/entry/607598 607598]]; also called Israeli Bedouin multiple contracture syndrome type A. LCCS2 is an autosomal recessive neurogenic form of a neonatally lethal arthrogryposis that is associated with atrophy of the anterior horn of the spinal cord. The LCCS2 syndrome is characterized by multiple joint contractures, anterior horn atrophy in the spinal cord, and a unique feature of a markedly distended urinary bladder. The phenotype suggests a spinal cord neuropathic etiology.<ref>PMID:17701904</ref>
| + | [https://www.uniprot.org/uniprot/ERBB3_HUMAN ERBB3_HUMAN] Defects in ERBB3 are the cause of lethal congenital contracture syndrome type 2 (LCCS2) [MIM:[https://omim.org/entry/607598 607598]; also called Israeli Bedouin multiple contracture syndrome type A. LCCS2 is an autosomal recessive neurogenic form of a neonatally lethal arthrogryposis that is associated with atrophy of the anterior horn of the spinal cord. The LCCS2 syndrome is characterized by multiple joint contractures, anterior horn atrophy in the spinal cord, and a unique feature of a markedly distended urinary bladder. The phenotype suggests a spinal cord neuropathic etiology.<ref>PMID:17701904</ref> |
| | == Function == | | == Function == |
| - | [[https://www.uniprot.org/uniprot/ERBB3_HUMAN ERBB3_HUMAN]] Binds and is activated by neuregulins and NTAK.<ref>PMID:15358134</ref>
| + | [https://www.uniprot.org/uniprot/ERBB3_HUMAN ERBB3_HUMAN] Binds and is activated by neuregulins and NTAK.<ref>PMID:15358134</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Receptor protein-tyrosine kinase]]
| + | [[Category: Agnew C]] |
| - | [[Category: Agnew, C]] | + | [[Category: Jura N]] |
| - | [[Category: Jura, N]] | + | [[Category: Littlefield P]] |
| - | [[Category: Littlefield, P]] | + | |
| - | [[Category: Bosutinib]]
| + | |
| - | [[Category: Membrane]]
| + | |
| - | [[Category: Pseudokinase]]
| + | |
| - | [[Category: Receptor tyrosine kinase]]
| + | |
| - | [[Category: Signaling protein]]
| + | |
| - | [[Category: Transferase-transferase inhibitor complex]]
| + | |
| Structural highlights
Disease
ERBB3_HUMAN Defects in ERBB3 are the cause of lethal congenital contracture syndrome type 2 (LCCS2) [MIM:607598; also called Israeli Bedouin multiple contracture syndrome type A. LCCS2 is an autosomal recessive neurogenic form of a neonatally lethal arthrogryposis that is associated with atrophy of the anterior horn of the spinal cord. The LCCS2 syndrome is characterized by multiple joint contractures, anterior horn atrophy in the spinal cord, and a unique feature of a markedly distended urinary bladder. The phenotype suggests a spinal cord neuropathic etiology.[1]
Function
ERBB3_HUMAN Binds and is activated by neuregulins and NTAK.[2]
Publication Abstract from PubMed
Effective inactivation of the HER2-HER3 tumor driver has remained elusive because of the challenging attributes of the pseudokinase HER3. We report a structure-function study of constitutive HER2-HER3 signaling to identify opportunities for targeting. The allosteric activation of the HER2 kinase domain (KD) by the HER3 KD is required for tumorigenic signaling and can potentially be targeted by allosteric inhibitors. ATP binding within the catalytically inactive HER3 KD provides structural rigidity that is important for signaling, but this is mimicked, not opposed, by small molecule ATP analogs, reported here in a bosutinib-bound crystal structure. Mutational disruption of ATP binding and molecular dynamics simulation of the apo KD of HER3 identify a conformational coupling of the ATP pocket with a hydrophobic AP-2 pocket, analogous to EGFR, that is critical for tumorigenic signaling and feasible for targeting. The value of these potential target sites is confirmed in tumor growth assays using gene replacement techniques.
Targetable HER3 functions driving tumorigenic signaling in HER2-amplified cancers.,Campbell MR, Ruiz-Saenz A, Peterson E, Agnew C, Ayaz P, Garfinkle S, Littlefield P, Steri V, Oeffinger J, Sampang M, Shan Y, Shaw DE, Jura N, Moasser MM Cell Rep. 2022 Feb 1;38(5):110291. doi: 10.1016/j.celrep.2021.110291. PMID:35108525[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Narkis G, Ofir R, Manor E, Landau D, Elbedour K, Birk OS. Lethal congenital contractural syndrome type 2 (LCCS2) is caused by a mutation in ERBB3 (Her3), a modulator of the phosphatidylinositol-3-kinase/Akt pathway. Am J Hum Genet. 2007 Sep;81(3):589-95. Epub 2007 Jul 24. PMID:17701904 doi:S0002-9297(07)61355-X
- ↑ Kinugasa Y, Ishiguro H, Tokita Y, Oohira A, Ohmoto H, Higashiyama S. Neuroglycan C, a novel member of the neuregulin family. Biochem Biophys Res Commun. 2004 Sep 3;321(4):1045-9. PMID:15358134 doi:10.1016/j.bbrc.2004.07.066
- ↑ Campbell MR, Ruiz-Saenz A, Peterson E, Agnew C, Ayaz P, Garfinkle S, Littlefield P, Steri V, Oeffinger J, Sampang M, Shan Y, Shaw DE, Jura N, Moasser MM. Targetable HER3 functions driving tumorigenic signaling in HER2-amplified cancers. Cell Rep. 2022 Feb 1;38(5):110291. doi: 10.1016/j.celrep.2021.110291. PMID:35108525 doi:http://dx.doi.org/10.1016/j.celrep.2021.110291
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