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6o39

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Revision as of 07:05, 17 April 2019

Crystal structure of Frizzled 5 CRD in complex with F2.I Fab

Structural highlights

6o39 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:	FZD5, C2orf31 (HUMAN)
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[FZD5_HUMAN] Receptor for Wnt proteins. Most of frizzled receptors are coupled to the beta-catenin canonical signaling pathway, which leads to the activation of disheveled proteins, inhibition of GSK-3 kinase, nuclear accumulation of beta-catenin and activation of Wnt target genes. A second signaling pathway involving PKC and calcium fluxes has been seen for some family members, but it is not yet clear if it represents a distinct pathway or if it can be integrated in the canonical pathway, as PKC seems to be required for Wnt-mediated inactivation of GSK-3 kinase. Both pathways seem to involve interactions with G-proteins. May be involved in transduction and intercellular transmission of polarity information during tissue morphogenesis and/or in differentiated tissues. Interacts specifically with Wnt5A to induce the beta-catenin pathway.^[1]

Publication Abstract from PubMed

Aberrant activation of Wnt/beta-catenin signaling occurs frequently in cancer. However, therapeutic targeting of this pathway is complicated by the role of Wnt in stem cell maintenance and tissue homeostasis. Here, we evaluated antibodies blocking 6 of the 10 human Wnt/Frizzled (FZD) receptors as potential therapeutics. Crystal structures revealed a common binding site for these monoclonal antibodies (mAbs) on FZD, blocking the interaction with the Wnt palmitoleic acid moiety. However, these mAbs displayed gastrointestinal toxicity or poor plasma exposure in vivo. Structure-guided engineering was used to refine the binding of each mAb for FZD receptors, resulting in antibody variants with improved in vivo tolerability and developability. Importantly, the lead variant mAb significantly inhibited tumor growth in the HPAF-II pancreatic tumor xenograft model. Taken together, our data demonstrate that anti-FZD cancer therapeutic antibodies with broad specificity can be fine-tuned to navigate in vivo exposure and tolerability while driving therapeutic efficacy.

Structure-guided design fine-tunes pharmacokinetics, tolerability, and antitumor profile of multispecific frizzled antibodies.,Raman S, Beilschmidt M, To M, Lin K, Lui F, Jmeian Y, Ng M, Fernandez M, Fu Y, Mascall K, Duque A, Wang X, Pan G, Angers S, Moffat J, Sidhu SS, Magram J, Sinclair AM, Fransson J, Julien JP Proc Natl Acad Sci U S A. 2019 Mar 20. pii: 1817246116. doi:, 10.1073/pnas.1817246116. PMID:30894493^[2]

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

References

↑ Hsieh JC, Rattner A, Smallwood PM, Nathans J. Biochemical characterization of Wnt-frizzled interactions using a soluble, biologically active vertebrate Wnt protein. Proc Natl Acad Sci U S A. 1999 Mar 30;96(7):3546-51. PMID:10097073
↑ Raman S, Beilschmidt M, To M, Lin K, Lui F, Jmeian Y, Ng M, Fernandez M, Fu Y, Mascall K, Duque A, Wang X, Pan G, Angers S, Moffat J, Sidhu SS, Magram J, Sinclair AM, Fransson J, Julien JP. Structure-guided design fine-tunes pharmacokinetics, tolerability, and antitumor profile of multispecific frizzled antibodies. Proc Natl Acad Sci U S A. 2019 Mar 20. pii: 1817246116. doi:, 10.1073/pnas.1817246116. PMID:30894493 doi:http://dx.doi.org/10.1073/pnas.1817246116

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/6o39"

@@ Line 3: / Line 3: @@
 <StructureSection load='6o39' size='340' side='right'caption='[[6o39]], [[Resolution|resolution]] 1.80&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6o39]] is a 3 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6O39 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6O39 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6o39]] is a 3 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=6O39 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6O39 FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">FZD5, C2orf31 ([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=6o39 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6o39 OCA], [http://pdbe.org/6o39 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6o39 RCSB], [http://www.ebi.ac.uk/pdbsum/6o39 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6o39 ProSAT]</span></td></tr>
 </table>
@@ Line 22: / Line 23: @@
 __TOC__
 </StructureSection>
+[[Category: Human]]
 [[Category: Large Structures]]
 [[Category: Beilschmidt, M]]

6o39

From Proteopedia

Revision as of 07:05, 17 April 2019

Crystal structure of Frizzled 5 CRD in complex with F2.I Fab

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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