4p59

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Revision as of 17:11, 4 January 2017

HER3 extracellular domain in complex with Fab fragment of MOR09825

Structural highlights

4p59 is a 3 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:	ERBB3, HER3 (HUMAN)
Activity:	Receptor protein-tyrosine kinase, with EC number 2.7.10.1
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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

HER2/HER3 dimerization resulting from overexpression of HER2 or neuregulin (NRG1) in cancer leads to HER3-mediated oncogenic activation of phosphoinositide 3-kinase (PI3K) signaling. Although ligand-blocking HER3 antibodies inhibit NRG1-driven tumor growth, they are ineffective against HER2-driven tumor growth because HER2 activates HER3 in a ligand-independent manner. In this study, we describe a novel HER3 monoclonal antibody (LJM716) that can neutralize multiple modes of HER3 activation, making it a superior candidate for clinical translation as a therapeutic candidate. LJM716 was a potent inhibitor of HER3/AKT phosphorylation and proliferation in HER2-amplified and NRG1-expressing cancer cells, and it displayed single-agent efficacy in tumor xenograft models. Combining LJM716 with agents that target HER2 or EGFR produced synergistic antitumor activity in vitro and in vivo. In particular, combining LJM716 with trastuzumab produced a more potent inhibition of signaling and cell proliferation than trastuzumab/pertuzumab combinations with similar activity in vivo. To elucidate its mechanism of action, we solved the structure of LJM716 bound to HER3, finding that LJM716 bound to an epitope, within domains 2 and 4, that traps HER3 in an inactive conformation. Taken together, our findings establish that LJM716 possesses a novel mechanism of action that, in combination with HER2- or EGFR-targeted agents, may leverage their clinical efficacy in ErbB-driven cancers.

An antibody that locks HER3 in the inactive conformation inhibits tumor growth driven by HER2 or neuregulin.,Garner AP, Bialucha CU, Sprague ER, Garrett JT, Sheng Q, Li S, Sineshchekova O, Saxena P, Sutton CR, Chen D, Chen Y, Wang H, Liang J, Das R, Mosher R, Gu J, Huang A, Haubst N, Zehetmeier C, Haberl M, Elis W, Kunz C, Heidt AB, Herlihy K, Murtie J, Schuller A, Arteaga CL, Sellers WR, Ettenberg SA Cancer Res. 2013 Oct 1;73(19):6024-35. doi: 10.1158/0008-5472.CAN-13-1198. Epub, 2013 Aug 8. PMID:23928993^[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
↑ Garner AP, Bialucha CU, Sprague ER, Garrett JT, Sheng Q, Li S, Sineshchekova O, Saxena P, Sutton CR, Chen D, Chen Y, Wang H, Liang J, Das R, Mosher R, Gu J, Huang A, Haubst N, Zehetmeier C, Haberl M, Elis W, Kunz C, Heidt AB, Herlihy K, Murtie J, Schuller A, Arteaga CL, Sellers WR, Ettenberg SA. An antibody that locks HER3 in the inactive conformation inhibits tumor growth driven by HER2 or neuregulin. Cancer Res. 2013 Oct 1;73(19):6024-35. doi: 10.1158/0008-5472.CAN-13-1198. Epub, 2013 Aug 8. PMID:23928993 doi:http://dx.doi.org/10.1158/0008-5472.CAN-13-1198

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/4p59"

@@ Line 1: / Line 1: @@
 ==HER3 extracellular domain in complex with Fab fragment of MOR09825==
 <StructureSection load='4p59' size='340' side='right' caption='[[4p59]], [[Resolution|resolution]] 3.40&Aring;' scene=''>
@@ Line 6: / Line 7: @@
 <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">ERBB3, HER3 ([http://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'>[http://en.wikipedia.org/wiki/Receptor_protein-tyrosine_kinase Receptor protein-tyrosine kinase], with EC number [http://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'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4p59 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4p59 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4p59 RCSB], [http://www.ebi.ac.uk/pdbsum/4p59 PDBsum]</span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4p59 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4p59 OCA], [http://pdbe.org/4p59 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4p59 RCSB], [http://www.ebi.ac.uk/pdbsum/4p59 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4p59 ProSAT]</span></td></tr>
 </table>
 == Disease ==
@@ Line 20: / Line 21: @@
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
+<div class="pdbe-citations 4p59" style="background-color:#fffaf0;"></div>
 == References ==
 <references/>

4p59

From Proteopedia

Revision as of 17:11, 4 January 2017

HER3 extracellular domain in complex with Fab fragment of MOR09825

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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