Structural basis of human LRG1 recognition by Magacizumab, a humanized monoclonal antibody with therapeutic potential.
Magacizumab
angiogenesis
antibody–antigen complex
cancer immunotherapy
leucine-rich α-2-glycoprotein 1
Journal
Acta crystallographica. Section D, Structural biology
ISSN: 2059-7983
Titre abrégé: Acta Crystallogr D Struct Biol
Pays: United States
ID NLM: 101676043
Informations de publication
Date de publication:
01 Jun 2022
01 Jun 2022
Historique:
received:
24
11
2021
accepted:
19
04
2022
entrez:
1
6
2022
pubmed:
2
6
2022
medline:
7
6
2022
Statut:
ppublish
Résumé
The formation of new dysfunctional blood vessels is a crucial stage in the development of various conditions such as macular degeneration, diabetes, cardiovascular disease, neurological disease and inflammatory disorders, as well as during tumor growth, eventually contributing to metastasis. An important factor involved in pathogenic angiogenesis is leucine-rich α-2-glycoprotein 1 (LRG1), the antibody blockade of which has been shown to lead to a reduction in both choroidal neovascularization and tumor growth in mouse models. In this work, the structural interactions between the LRG1 epitope and the Fab fragment of Magacizumab, a humanized function-blocking IgG4 against LRG1, are analysed, determining its specific binding mode and the key residues involved in LRG1 recognition. Based on these structural findings, a series of mutations are suggested that could be introduced into Magacizumab to increase its affinity for LRG1, as well as a model of the entire Fab-LRG1 complex that could enlighten new strategies to enhance affinity, consequently leading towards an even more efficient therapeutic.
Identifiants
pubmed: 35647920
pii: S2059798322004132
doi: 10.1107/S2059798322004132
pmc: PMC9159282
doi:
Substances chimiques
Antibodies, Monoclonal, Humanized
0
Glycoproteins
0
LRG1 protein, human
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
725-734Subventions
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : Worldwide Cancer Research
ID : 101944001
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 203859/Z/16/Z
Pays : United Kingdom
Informations de copyright
open access.
Références
Sci Transl Med. 2021 Sep;13(609):eabe6805
pubmed: 34516824
Cell. 2011 Sep 16;146(6):873-87
pubmed: 21925313
Bioinformatics. 2007 Dec 15;23(24):3403-5
pubmed: 17921170
Acta Crystallogr D Biol Crystallogr. 2010 Jan;66(Pt 1):12-21
pubmed: 20057044
Proteins. 2018 May;86(5):495-500
pubmed: 29490423
Nucleic Acids Res. 2013 Jan;41(Database issue):D344-7
pubmed: 23161676
Acta Crystallogr D Biol Crystallogr. 2010 Apr;66(Pt 4):486-501
pubmed: 20383002
EMBO J. 2011 Sep 23;30(21):4479-88
pubmed: 21946559
Nat Struct Mol Biol. 2015 Dec;22(12):953-8
pubmed: 26595420
J Appl Crystallogr. 2007 Aug 1;40(Pt 4):658-674
pubmed: 19461840
Nature. 2000 Sep 14;407(6801):249-57
pubmed: 11001068
Med (N Y). 2021 Nov 12;2(11):1231-1252.e10
pubmed: 35590198
Nat Mach Intell. 2021 Jul;3:601-609
pubmed: 34368623
Acta Crystallogr D Biol Crystallogr. 2011 Apr;67(Pt 4):235-42
pubmed: 21460441
Science. 2015 Nov 6;350(6261):680-4
pubmed: 26542571
Acta Crystallogr D Biol Crystallogr. 2011 Apr;67(Pt 4):282-92
pubmed: 21460446
J Exp Med. 2009 Jul 6;206(7):1465-72
pubmed: 19564350
Nature. 2013 Jul 18;499(7458):306-11
pubmed: 23868260
Nature. 2021 Aug;596(7873):583-589
pubmed: 34265844
J Biol Chem. 2017 Jul 28;292(30):12713-12724
pubmed: 28623233
J Invest Dermatol. 2020 Feb;140(2):455-464.e8
pubmed: 31344385
J Mol Biol. 2007 Sep 21;372(3):774-97
pubmed: 17681537
Nucleic Acids Res. 2019 Jul 2;47(W1):W402-W407
pubmed: 31251384
Bioinformatics. 2009 May 1;25(9):1189-91
pubmed: 19151095
Acta Crystallogr D Struct Biol. 2019 Oct 1;75(Pt 10):861-877
pubmed: 31588918
Nucleic Acids Res. 2019 Jul 2;47(W1):W636-W641
pubmed: 30976793
Acta Crystallogr D Biol Crystallogr. 2010 Feb;66(Pt 2):125-32
pubmed: 20124692
Nucleic Acids Res. 2018 Jul 2;46(W1):W296-W303
pubmed: 29788355
Biochemistry. 2020 Sep 22;59(37):3401-3410
pubmed: 32845612
Acta Crystallogr D Biol Crystallogr. 2000 Apr;56(Pt 4):442-50
pubmed: 10739917
J Synchrotron Radiat. 2014 Jul;21(Pt 4):679-89
pubmed: 24971961
Curr Protein Pept Sci. 2006 Jun;7(3):217-27
pubmed: 16787261
Proteins. 2011;79 Suppl 10:161-71
pubmed: 21987485
J Exp Med. 2021 Aug 2;218(8):
pubmed: 34287647
J Synchrotron Radiat. 2000 Sep 1;7(Pt 5):313-7
pubmed: 16609214
Biochem Biophys Res Commun. 2009 May 15;382(4):776-9
pubmed: 19324010
Acta Crystallogr D Biol Crystallogr. 1999 Jun;55(Pt 6):1158-67
pubmed: 10329778
J Mol Biol. 1990 Oct 5;215(3):403-10
pubmed: 2231712
Front Cell Dev Biol. 2021 Oct 08;9:744908
pubmed: 34692699
J Mol Biol. 1999 Nov 5;293(4):865-81
pubmed: 10543973