6i07

From Proteopedia

(Difference between revisions)

Revision as of 08:18, 3 April 2019

Crystal structure of EpCAM in complex with scFv

Structural highlights

6i07 is a 4 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
NonStd Res:
Gene:	EPCAM, GA733-2, M1S2, M4S1, MIC18, TACSTD1, TROP1 (HUMAN)
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

[EPCAM_HUMAN] Intestinal epithelial dysplasia;Hereditary nonpolyposis colon cancer. The disease is caused by mutations affecting the gene represented in this entry.^[1] The disease is caused by mutations affecting the gene represented in this entry. HNPCC8 results from heterozygous deletion of 3-prime exons of EPCAM and intergenic regions directly upstream of MSH2, resulting in transcriptional read-through and epigenetic silencing of MSH2 in tissues expressing EPCAM.^[2]

Function

[EPCAM_HUMAN] May act as a physical homophilic interaction molecule between intestinal epithelial cells (IECs) and intraepithelial lymphocytes (IELs) at the mucosal epithelium for providing immunological barrier as a first line of defense against mucosal infection. Plays a role in embryonic stem cells proliferation and differentiation. Up-regulates the expression of FABP5, MYC and cyclins A and E.^[3] ^[4] ^[5] ^[6]

Publication Abstract from PubMed

Activation of the Met receptor tyrosine kinase, either by its ligand, hepatocyte growth factor (HGF), or via ligand-independent mechanisms, such as MET amplification or receptor overexpression, has been implicated in driving tumor proliferation, metastasis, and resistance to therapy. Clinical development of Met-targeted antibodies has been challenging, however, as bivalent antibodies exhibit agonistic properties, whereas monovalent antibodies lack potency and the capacity to down-regulate Met. Through computational modeling, we found that the potency of a monovalent antibody targeting Met could be dramatically improved by introducing a second binding site that recognizes an unrelated, highly expressed antigen on the tumor cell surface. Guided by this prediction, we engineered MM-131, a bispecific antibody that is monovalent for both Met and epithelial cell adhesion molecule (EpCAM). MM-131 is a purely antagonistic antibody that blocks ligand-dependent and ligand-independent Met signaling by inhibiting HGF binding to Met and inducing receptor down-regulation. Together, these mechanisms lead to inhibition of proliferation in Met-driven cancer cells, inhibition of HGF-mediated cancer cell migration, and inhibition of tumor growth in HGF-dependent and -independent mouse xenograft models. Consistent with its design, MM-131 is more potent in EpCAM-high cells than in EpCAM-low cells, and its potency decreases when EpCAM levels are reduced by RNAi. Evaluation of Met, EpCAM, and HGF levels in human tumor samples reveals that EpCAM is expressed at high levels in a wide range of Met-positive tumor types, suggesting a broad opportunity for clinical development of MM-131.

MM-131, a bispecific anti-Met/EpCAM mAb, inhibits HGF-dependent and HGF-independent Met signaling through concurrent binding to EpCAM.,Casaletto JB, Geddie ML, Abu-Yousif AO, Masson K, Fulgham A, Boudot A, Maiwald T, Kearns JD, Kohli N, Su S, Razlog M, Raue A, Kalra A, Hakansson M, Logan DT, Welin M, Chattopadhyay S, Harms BD, Nielsen UB, Schoeberl B, Lugovskoy AA, MacBeath G Proc Natl Acad Sci U S A. 2019 Mar 21. pii: 1819085116. doi:, 10.1073/pnas.1819085116. PMID:30898885^[7]

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

References

↑ Sivagnanam M, Mueller JL, Lee H, Chen Z, Nelson SF, Turner D, Zlotkin SH, Pencharz PB, Ngan BY, Libiger O, Schork NJ, Lavine JE, Taylor S, Newbury RO, Kolodner RD, Hoffman HM. Identification of EpCAM as the gene for congenital tufting enteropathy. Gastroenterology. 2008 Aug;135(2):429-37. doi: 10.1053/j.gastro.2008.05.036. Epub, 2008 May 15. PMID:18572020 doi:http://dx.doi.org/10.1053/j.gastro.2008.05.036
↑ Ligtenberg MJ, Kuiper RP, Chan TL, Goossens M, Hebeda KM, Voorendt M, Lee TY, Bodmer D, Hoenselaar E, Hendriks-Cornelissen SJ, Tsui WY, Kong CK, Brunner HG, van Kessel AG, Yuen ST, van Krieken JH, Leung SY, Hoogerbrugge N. Heritable somatic methylation and inactivation of MSH2 in families with Lynch syndrome due to deletion of the 3' exons of TACSTD1. Nat Genet. 2009 Jan;41(1):112-7. doi: 10.1038/ng.283. Epub 2008 Dec 21. PMID:19098912 doi:http://dx.doi.org/10.1038/ng.283
↑ Munz M, Kieu C, Mack B, Schmitt B, Zeidler R, Gires O. The carcinoma-associated antigen EpCAM upregulates c-myc and induces cell proliferation. Oncogene. 2004 Jul 29;23(34):5748-58. PMID:15195135 doi:http://dx.doi.org/10.1038/sj.onc.1207610
↑ Munz M, Zeidler R, Gires O. The tumour-associated antigen EpCAM upregulates the fatty acid binding protein E-FABP. Cancer Lett. 2005 Jul 8;225(1):151-7. Epub 2004 Dec 28. PMID:15922867 doi:http://dx.doi.org/10.1016/j.canlet.2004.11.048
↑ Lu TY, Lu RM, Liao MY, Yu J, Chung CH, Kao CF, Wu HC. Epithelial cell adhesion molecule regulation is associated with the maintenance of the undifferentiated phenotype of human embryonic stem cells. J Biol Chem. 2010 Mar 19;285(12):8719-32. doi: 10.1074/jbc.M109.077081. Epub 2010, Jan 11. PMID:20064925 doi:http://dx.doi.org/10.1074/jbc.M109.077081
↑ Ng VY, Ang SN, Chan JX, Choo AB. Characterization of epithelial cell adhesion molecule as a surface marker on undifferentiated human embryonic stem cells. Stem Cells. 2010 Jan;28(1):29-35. doi: 10.1002/stem.221. PMID:19785009 doi:http://dx.doi.org/10.1002/stem.221
↑ Casaletto JB, Geddie ML, Abu-Yousif AO, Masson K, Fulgham A, Boudot A, Maiwald T, Kearns JD, Kohli N, Su S, Razlog M, Raue A, Kalra A, Hakansson M, Logan DT, Welin M, Chattopadhyay S, Harms BD, Nielsen UB, Schoeberl B, Lugovskoy AA, MacBeath G. MM-131, a bispecific anti-Met/EpCAM mAb, inhibits HGF-dependent and HGF-independent Met signaling through concurrent binding to EpCAM. Proc Natl Acad Sci U S A. 2019 Mar 21. pii: 1819085116. doi:, 10.1073/pnas.1819085116. PMID:30898885 doi:http://dx.doi.org/10.1073/pnas.1819085116

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/6i07"

@@ Line 3: / Line 3: @@
 <StructureSection load='6i07' size='340' side='right'caption='[[6i07]], [[Resolution|resolution]] 2.35&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6i07]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6I07 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6I07 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6i07]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6I07 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6I07 FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></td></tr>
 <tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=PCA:PYROGLUTAMIC+ACID'>PCA</scene></td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">EPCAM, GA733-2, M1S2, M4S1, MIC18, TACSTD1, TROP1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=6i07 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6i07 OCA], [http://pdbe.org/6i07 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6i07 RCSB], [http://www.ebi.ac.uk/pdbsum/6i07 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6i07 ProSAT]</span></td></tr>
 </table>
@@ Line 12: / Line 13: @@
 == Function ==
 [[http://www.uniprot.org/uniprot/EPCAM_HUMAN EPCAM_HUMAN]] May act as a physical homophilic interaction molecule between intestinal epithelial cells (IECs) and intraepithelial lymphocytes (IELs) at the mucosal epithelium for providing immunological barrier as a first line of defense against mucosal infection. Plays a role in embryonic stem cells proliferation and differentiation. Up-regulates the expression of FABP5, MYC and cyclins A and E.<ref>PMID:15195135</ref> <ref>PMID:15922867</ref> <ref>PMID:20064925</ref> <ref>PMID:19785009</ref>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+Activation of the Met receptor tyrosine kinase, either by its ligand, hepatocyte growth factor (HGF), or via ligand-independent mechanisms, such as MET amplification or receptor overexpression, has been implicated in driving tumor proliferation, metastasis, and resistance to therapy. Clinical development of Met-targeted antibodies has been challenging, however, as bivalent antibodies exhibit agonistic properties, whereas monovalent antibodies lack potency and the capacity to down-regulate Met. Through computational modeling, we found that the potency of a monovalent antibody targeting Met could be dramatically improved by introducing a second binding site that recognizes an unrelated, highly expressed antigen on the tumor cell surface. Guided by this prediction, we engineered MM-131, a bispecific antibody that is monovalent for both Met and epithelial cell adhesion molecule (EpCAM). MM-131 is a purely antagonistic antibody that blocks ligand-dependent and ligand-independent Met signaling by inhibiting HGF binding to Met and inducing receptor down-regulation. Together, these mechanisms lead to inhibition of proliferation in Met-driven cancer cells, inhibition of HGF-mediated cancer cell migration, and inhibition of tumor growth in HGF-dependent and -independent mouse xenograft models. Consistent with its design, MM-131 is more potent in EpCAM-high cells than in EpCAM-low cells, and its potency decreases when EpCAM levels are reduced by RNAi. Evaluation of Met, EpCAM, and HGF levels in human tumor samples reveals that EpCAM is expressed at high levels in a wide range of Met-positive tumor types, suggesting a broad opportunity for clinical development of MM-131.
+MM-131, a bispecific anti-Met/EpCAM mAb, inhibits HGF-dependent and HGF-independent Met signaling through concurrent binding to EpCAM.,Casaletto JB, Geddie ML, Abu-Yousif AO, Masson K, Fulgham A, Boudot A, Maiwald T, Kearns JD, Kohli N, Su S, Razlog M, Raue A, Kalra A, Hakansson M, Logan DT, Welin M, Chattopadhyay S, Harms BD, Nielsen UB, Schoeberl B, Lugovskoy AA, MacBeath G Proc Natl Acad Sci U S A. 2019 Mar 21. pii: 1819085116. doi:, 10.1073/pnas.1819085116. PMID:30898885<ref>PMID:30898885</ref>
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+</div>
+<div class="pdbe-citations 6i07" style="background-color:#fffaf0;"></div>
 == References ==
 <references/>
 __TOC__
 </StructureSection>
+[[Category: Human]]
 [[Category: Large Structures]]
 [[Category: Abu-Yousif, A O]]

6i07

From Proteopedia

Revision as of 08:18, 3 April 2019

Crystal structure of EpCAM in complex with scFv

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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