5fuo: Difference between revisions
New page: '''Unreleased structure''' The entry 5fuo is ON HOLD Authors: Adams, R., Ceska, T. Description: Extending the half-life of a Fab fragment through generation of a humanised anti-Human S... |
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==Extending the half-life of a Fab fragment through generation of a humanised anti-Human Serum Albumin (HSA) Fv domain: an investigation into the correlation between affinity and serum half-life== | |||
<StructureSection load='5fuo' size='340' side='right'caption='[[5fuo]], [[Resolution|resolution]] 3.60Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[5fuo]] is a 3 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=5FUO OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5FUO FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3.6Å</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=5fuo FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5fuo OCA], [https://pdbe.org/5fuo PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5fuo RCSB], [https://www.ebi.ac.uk/pdbsum/5fuo PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5fuo ProSAT]</span></td></tr> | |||
</table> | |||
== Disease == | |||
[https://www.uniprot.org/uniprot/ALBU_HUMAN ALBU_HUMAN] Defects in ALB are a cause of familial dysalbuminemic hyperthyroxinemia (FDH) [MIM:[https://omim.org/entry/103600 103600]. FDH is a form of euthyroid hyperthyroxinemia that is due to increased affinity of ALB for T(4). It is the most common cause of inherited euthyroid hyperthyroxinemia in Caucasian population.<ref>PMID:8048949</ref> <ref>PMID:7852505</ref> <ref>PMID:9329347</ref> <ref>PMID:9589637</ref> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/ALBU_HUMAN ALBU_HUMAN] Serum albumin, the main protein of plasma, has a good binding capacity for water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs. Its main function is the regulation of the colloidal osmotic pressure of blood. Major zinc transporter in plasma, typically binds about 80% of all plasma zinc.<ref>PMID:19021548</ref> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
We generated an anti-albumin antibody, CA645, to link its Fv domain to an antigen-binding fragment (Fab), thereby extending the serum half-life of the Fab. CA645 was demonstrated to bind human, cynomolgus, and mouse serum albumin with similar affinity (1-7 nM), and to bind human serum albumin (HSA) when it is in complex with common known ligands. Importantly for half-life extension, CA645 binds HSA with similar affinity within the physiologically relevant range of pH 5.0 - pH 7.4, and does not have a deleterious effect on the binding of HSA to neonatal Fc receptor (FcRn). A crystal structure of humanized CA645 Fab in complex with HSA was solved and showed that CA645 Fab binds to domain II of HSA. Superimposition with the crystal structure of FcRn bound to HSA confirmed that CA645 does not block HSA binding to FcRn. In mice, the serum half-life of humanized CA645 Fab is 84.2 h. This is a significant extension in comparison with < 1 h for a non-HSA binding CA645 Fab variant. The Fab-HSA structure was used to design a series of mutants with reduced affinity to investigate the correlation between the affinity for albumin and serum half-life. Reduction in the affinity for MSA by 144-fold from 2.2 nM to 316 nM had no effect on serum half-life. Strikingly, despite a reduction in affinity to 62 microM, an extension in serum half-life of 26.4 h was still obtained. CA645 Fab and the CA645 Fab-HSA complex have been deposited in the Protein Data Bank (PDB) with accession codes, 5FUZ and 5FUO, respectively. | |||
Extending the half-life of a fab fragment through generation of a humanized anti-human serum albumin fv domain: An investigation into the correlation between affinity and serum half-life.,Adams R, Griffin L, Compson JE, Jairaj M, Baker T, Ceska T, West S, Zaccheo O, Dave E, Lawson AD, Humphreys DP, Heywood S MAbs. 2016 Jun 17:1-11. PMID:27315033<ref>PMID:27315033</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: Adams | <div class="pdbe-citations 5fuo" style="background-color:#fffaf0;"></div> | ||
[[Category: Ceska | |||
==See Also== | |||
*[[Albumin 3D structures|Albumin 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Adams R]] | |||
[[Category: Ceska T]] | |||
Latest revision as of 16:27, 26 July 2023
Extending the half-life of a Fab fragment through generation of a humanised anti-Human Serum Albumin (HSA) Fv domain: an investigation into the correlation between affinity and serum half-lifeExtending the half-life of a Fab fragment through generation of a humanised anti-Human Serum Albumin (HSA) Fv domain: an investigation into the correlation between affinity and serum half-life
Structural highlights
DiseaseALBU_HUMAN Defects in ALB are a cause of familial dysalbuminemic hyperthyroxinemia (FDH) [MIM:103600. FDH is a form of euthyroid hyperthyroxinemia that is due to increased affinity of ALB for T(4). It is the most common cause of inherited euthyroid hyperthyroxinemia in Caucasian population.[1] [2] [3] [4] FunctionALBU_HUMAN Serum albumin, the main protein of plasma, has a good binding capacity for water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs. Its main function is the regulation of the colloidal osmotic pressure of blood. Major zinc transporter in plasma, typically binds about 80% of all plasma zinc.[5] Publication Abstract from PubMedWe generated an anti-albumin antibody, CA645, to link its Fv domain to an antigen-binding fragment (Fab), thereby extending the serum half-life of the Fab. CA645 was demonstrated to bind human, cynomolgus, and mouse serum albumin with similar affinity (1-7 nM), and to bind human serum albumin (HSA) when it is in complex with common known ligands. Importantly for half-life extension, CA645 binds HSA with similar affinity within the physiologically relevant range of pH 5.0 - pH 7.4, and does not have a deleterious effect on the binding of HSA to neonatal Fc receptor (FcRn). A crystal structure of humanized CA645 Fab in complex with HSA was solved and showed that CA645 Fab binds to domain II of HSA. Superimposition with the crystal structure of FcRn bound to HSA confirmed that CA645 does not block HSA binding to FcRn. In mice, the serum half-life of humanized CA645 Fab is 84.2 h. This is a significant extension in comparison with < 1 h for a non-HSA binding CA645 Fab variant. The Fab-HSA structure was used to design a series of mutants with reduced affinity to investigate the correlation between the affinity for albumin and serum half-life. Reduction in the affinity for MSA by 144-fold from 2.2 nM to 316 nM had no effect on serum half-life. Strikingly, despite a reduction in affinity to 62 microM, an extension in serum half-life of 26.4 h was still obtained. CA645 Fab and the CA645 Fab-HSA complex have been deposited in the Protein Data Bank (PDB) with accession codes, 5FUZ and 5FUO, respectively. Extending the half-life of a fab fragment through generation of a humanized anti-human serum albumin fv domain: An investigation into the correlation between affinity and serum half-life.,Adams R, Griffin L, Compson JE, Jairaj M, Baker T, Ceska T, West S, Zaccheo O, Dave E, Lawson AD, Humphreys DP, Heywood S MAbs. 2016 Jun 17:1-11. PMID:27315033[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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