OCA at 14:16, 18 October 2023

OCA — Wed, 18 Oct 2023 14:16:02 GMT

←Older revision		Revision as of 14:16, 18 October 2023
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	==Brain delivery of therapeutic proteins using an Fc fragment blood-brain barrier transport vehicle in mice and monkeys==		==Brain delivery of therapeutic proteins using an Fc fragment blood-brain barrier transport vehicle in mice and monkeys==
-	<StructureSection load='6w3h' size='340' side='right'caption='[[6w3h]]' scene=''>	+	<StructureSection load='6w3h' size='340' side='right'caption='[[6w3h]], [[Resolution\|resolution]] 3.38Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6W3H OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://proteopedia.org/fgij/fg.htm?mol=6W3H FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[6w3h]] is a 4 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=6W3H OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6W3H FirstGlance]. <br>
-	</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[~~http~~://proteopedia.org/fgij/fg.htm?mol=6w3h FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6w3h OCA], [~~http~~://pdbe.org/6w3h PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=6w3h RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/6w3h PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=6w3h ProSAT]</span></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]] 3.38Å</td></tr>
		+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BMA:BETA-D-MANNOSE'>BMA</scene>, <scene name='pdbligand=MAN:ALPHA-D-MANNOSE'>MAN</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</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=6w3h FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6w3h OCA], [https://pdbe.org/6w3h PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6w3h RCSB], [https://www.ebi.ac.uk/pdbsum/6w3h PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6w3h ProSAT]</span></td></tr>
	</table>		</table>
		+	== Function ==
		+	[https://www.uniprot.org/uniprot/TFR1_HUMAN TFR1_HUMAN] Cellular uptake of iron occurs via receptor-mediated endocytosis of ligand-occupied transferrin receptor into specialized endosomes. Endosomal acidification leads to iron release. The apotransferrin-receptor complex is then recycled to the cell surface with a return to neutral pH and the concomitant loss of affinity of apotransferrin for its receptor. Transferrin receptor is necessary for development of erythrocytes and the nervous system (By similarity). A second ligand, the heditary hemochromatosis protein HFE, competes for binding with transferrin for an overlapping C-terminal binding site.<ref>PMID:3568132</ref>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	Effective delivery of protein therapeutics to the central nervous system (CNS) has been greatly restricted by the blood-brain barrier (BBB). We describe the development of a BBB transport vehicle (TV) comprising an engineered Fc fragment that exploits receptor-mediated transcytosis for CNS delivery of biotherapeutics by binding a highly expressed brain endothelial cell target. TVs were engineered using directed evolution to bind the apical domain of the human transferrin receptor (hTfR) without the use of amino acid insertions, deletions, or unnatural appendages. A crystal structure of the TV-TfR complex revealed the TV binding site to be away from transferrin and FcRn binding sites, which was further confirmed experimentally in vitro and in vivo. Recombinant expression of TVs fused to anti-beta-secretase (BACE1) Fabs yielded antibody transport vehicle (ATV) molecules with native immunoglobulin G (IgG) structure and stability. Peripheral administration of anti-BACE1 ATVs to hTfR-engineered mice and cynomolgus monkeys resulted in substantially improved CNS uptake and sustained pharmacodynamic responses. The TV platform readily accommodates numerous additional configurations, including bispecific antibodies and protein fusions, yielding a highly modular CNS delivery platform.
		+
		+	Brain delivery of therapeutic proteins using an Fc fragment blood-brain barrier transport vehicle in mice and monkeys.,Kariolis MS, Wells RC, Getz JA, Kwan W, Mahon CS, Tong R, Kim DJ, Srivastava A, Bedard C, Henne KR, Giese T, Assimon VA, Chen X, Zhang Y, Solanoy H, Jenkins K, Sanchez PE, Kane L, Miyamoto T, Chew KS, Pizzo ME, Liang N, Calvert MEK, DeVos SL, Baskaran S, Hall S, Sweeney ZK, Thorne RG, Watts RJ, Dennis MS, Silverman AP, Zuchero YJY Sci Transl Med. 2020 May 27;12(545). pii: 12/545/eaay1359. doi:, 10.1126/scitranslmed.aay1359. PMID:32461332<ref>PMID:32461332</ref>
		+
		+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
		+	</div>
		+	<div class="pdbe-citations 6w3h" style="background-color:#fffaf0;"></div>
		+	== References ==
		+	<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Homo sapiens]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
	[[Category: Kariolis M]]		[[Category: Kariolis M]]
	[[Category: Srivastava A]]		[[Category: Srivastava A]]
	[[Category: Wells R]]		[[Category: Wells R]]

OCA at 06:28, 10 June 2020

OCA — Wed, 10 Jun 2020 06:28:27 GMT

←Older revision		Revision as of 06:28, 10 June 2020
Line 1:		Line 1:
-	'''Unreleased structure'''

-	~~The entry~~ 6w3h is ~~ON HOLD~~	+	==Brain delivery of therapeutic proteins using an Fc fragment blood-brain barrier transport vehicle in mice and monkeys==
-		+	<StructureSection load='6w3h' size='340' side='right'caption='[[6w3h]]' scene=''>
-	~~Authors~~:	+	== Structural highlights ==
-		+	<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6W3H OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6W3H FirstGlance]. <br>
-	~~Description~~:	+	</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6w3h FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6w3h OCA], [http://pdbe.org/6w3h PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6w3h RCSB], [http://www.ebi.ac.uk/pdbsum/6w3h PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6w3h ProSAT]</span></td></tr>
-	[[Category: ~~Unreleased Structures~~]]	+	</table>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Large Structures]]
		+	[[Category: Kariolis M]]
		+	[[Category: Srivastava A]]
		+	[[Category: Wells R]]

OCA: Protected "6w3h" [edit=sysop:move=sysop]

OCA — Wed, 18 Mar 2020 08:32:15 GMT

Protected "6w3h" [edit=sysop:move=sysop]

←Older revision

Revision as of 08:32, 18 March 2020

OCA: New page: '''Unreleased structure''' The entry 6w3h is ON HOLD Authors: Description: Category: Unreleased Structures

OCA — Wed, 18 Mar 2020 08:32:14 GMT

New page: '''Unreleased structure''' The entry 6w3h is ON HOLD Authors: Description: Category: Unreleased Structures

New page

'''Unreleased structure'''

The entry 6w3h is ON HOLD

Authors:

Description:
[[Category: Unreleased Structures]]

6w3h - Revision history

OCA at 14:16, 18 October 2023

OCA at 06:28, 10 June 2020

OCA: Protected "6w3h" [edit=sysop:move=sysop]

OCA: New page: '''Unreleased structure''' The entry 6w3h is ON HOLD Authors: Description: Category: Unreleased Structures