Structural basis for the inhibition of βFXIIa by garadacimab

Activated FXII (FXIIa) is the principal initiator of the plasma contact system and can activate both procoagulant and proinflammatory pathways. Its activity is important in the pathophysiology of hereditary angioedema (HAE). Here, we describe a high-resolution cryoelectron microscopy (cryo-EM) struc...

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Published inStructure (London) Vol. 32; no. 10; pp. 1705 - 1710.e3
Main Authors Drulyte, Ieva, Ghai, Rajesh, Ow, Saw Yen, Kapp, Eugene A., Quek, Adam J., Panousis, Con, Wilson, Michael J., Nash, Andrew D., Pelzing, Matthias
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LanguageEnglish
Published United States Elsevier Inc 03.10.2024
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Abstract Activated FXII (FXIIa) is the principal initiator of the plasma contact system and can activate both procoagulant and proinflammatory pathways. Its activity is important in the pathophysiology of hereditary angioedema (HAE). Here, we describe a high-resolution cryoelectron microscopy (cryo-EM) structure of the beta-chain from FXIIa (βFXIIa) complexed with the Fab fragment of garadacimab. Garadacimab binds to βFXIIa through an unusually long CDR-H3 that inserts into the S1 pocket in a non-canonical way. This structural mechanism is likely the primary contributor to the inhibition of activated FXIIa proteolytic activity in HAE. Garadacimab Fab-βFXIIa structure also reveals critical determinants of high-affinity binding of garadacimab to activated FXIIa. Structural analysis with other bona fide FXIIa inhibitors, such as benzamidine and C1-INH, reveals a surprisingly similar mechanism of βFXIIa inhibition by garadacimab. In summary, the garadacimab Fab-βFXIIa structure provides crucial insights into its mechanism of action and delineates primary and auxiliary paratopes/epitopes. [Display omitted] •Structure of therapeutic antibody garadacimab’s Fab fragment complexed with βFXIIa•CDR-H3 insertion into the catalytic cleft of βFXIIa inhibits proteolytic activity•Structural basis for the high-affinity binding of garadacimab to βFXIIa is revealed•Garadacimab employs an inhibition mechanism similar to endogenous inhibitor C1-INH Drulyte et al. determined the high-resolution cryo-EM structure of the Fab fragment of garadacimab in complex with the beta-chain from activated FXIIa (βFXIIa). The structure reveals the molecular interactions responsible for their high-affinity binding and provides insights into the mechanism of proteolytic inhibition.
AbstractList Activated FXII (FXIIa) is the principal initiator of the plasma contact system and can activate both procoagulant and proinflammatory pathways. Its activity is important in the pathophysiology of hereditary angioedema (HAE). Here, we describe a high-resolution cryoelectron microscopy (cryo-EM) structure of the beta-chain from FXIIa (βFXIIa) complexed with the Fab fragment of garadacimab. Garadacimab binds to βFXIIa through an unusually long CDR-H3 that inserts into the S1 pocket in a non-canonical way. This structural mechanism is likely the primary contributor to the inhibition of activated FXIIa proteolytic activity in HAE. Garadacimab Fab-βFXIIa structure also reveals critical determinants of high-affinity binding of garadacimab to activated FXIIa. Structural analysis with other bona fide FXIIa inhibitors, such as benzamidine and C1-INH, reveals a surprisingly similar mechanism of βFXIIa inhibition by garadacimab. In summary, the garadacimab Fab-βFXIIa structure provides crucial insights into its mechanism of action and delineates primary and auxiliary paratopes/epitopes.
Activated FXII (FXIIa) is the principal initiator of the plasma contact system and can activate both procoagulant and proinflammatory pathways. Its activity is important in the pathophysiology of hereditary angioedema (HAE). Here, we describe a high-resolution cryoelectron microscopy (cryo-EM) structure of the beta-chain from FXIIa (βFXIIa) complexed with the Fab fragment of garadacimab. Garadacimab binds to βFXIIa through an unusually long CDR-H3 that inserts into the S1 pocket in a non-canonical way. This structural mechanism is likely the primary contributor to the inhibition of activated FXIIa proteolytic activity in HAE. Garadacimab Fab-βFXIIa structure also reveals critical determinants of high-affinity binding of garadacimab to activated FXIIa. Structural analysis with other bona fide FXIIa inhibitors, such as benzamidine and C1-INH, reveals a surprisingly similar mechanism of βFXIIa inhibition by garadacimab. In summary, the garadacimab Fab-βFXIIa structure provides crucial insights into its mechanism of action and delineates primary and auxiliary paratopes/epitopes. [Display omitted] •Structure of therapeutic antibody garadacimab’s Fab fragment complexed with βFXIIa•CDR-H3 insertion into the catalytic cleft of βFXIIa inhibits proteolytic activity•Structural basis for the high-affinity binding of garadacimab to βFXIIa is revealed•Garadacimab employs an inhibition mechanism similar to endogenous inhibitor C1-INH Drulyte et al. determined the high-resolution cryo-EM structure of the Fab fragment of garadacimab in complex with the beta-chain from activated FXIIa (βFXIIa). The structure reveals the molecular interactions responsible for their high-affinity binding and provides insights into the mechanism of proteolytic inhibition.
Activated FXII (FXIIa) is the principal initiator of the plasma contact system and can activate both procoagulant and proinflammatory pathways. Its activity is important in the pathophysiology of hereditary angioedema (HAE). Here, we describe a high-resolution cryoelectron microscopy (cryo-EM) structure of the beta-chain from FXIIa (βFXIIa) complexed with the Fab fragment of garadacimab. Garadacimab binds to βFXIIa through an unusually long CDR-H3 that inserts into the S1 pocket in a non-canonical way. This structural mechanism is likely the primary contributor to the inhibition of activated FXIIa proteolytic activity in HAE. Garadacimab Fab-βFXIIa structure also reveals critical determinants of high-affinity binding of garadacimab to activated FXIIa. Structural analysis with other bona fide FXIIa inhibitors, such as benzamidine and C1-INH, reveals a surprisingly similar mechanism of βFXIIa inhibition by garadacimab. In summary, the garadacimab Fab-βFXIIa structure provides crucial insights into its mechanism of action and delineates primary and auxiliary paratopes/epitopes.Activated FXII (FXIIa) is the principal initiator of the plasma contact system and can activate both procoagulant and proinflammatory pathways. Its activity is important in the pathophysiology of hereditary angioedema (HAE). Here, we describe a high-resolution cryoelectron microscopy (cryo-EM) structure of the beta-chain from FXIIa (βFXIIa) complexed with the Fab fragment of garadacimab. Garadacimab binds to βFXIIa through an unusually long CDR-H3 that inserts into the S1 pocket in a non-canonical way. This structural mechanism is likely the primary contributor to the inhibition of activated FXIIa proteolytic activity in HAE. Garadacimab Fab-βFXIIa structure also reveals critical determinants of high-affinity binding of garadacimab to activated FXIIa. Structural analysis with other bona fide FXIIa inhibitors, such as benzamidine and C1-INH, reveals a surprisingly similar mechanism of βFXIIa inhibition by garadacimab. In summary, the garadacimab Fab-βFXIIa structure provides crucial insights into its mechanism of action and delineates primary and auxiliary paratopes/epitopes.
Author Kapp, Eugene A.
Wilson, Michael J.
Panousis, Con
Nash, Andrew D.
Ghai, Rajesh
Ow, Saw Yen
Quek, Adam J.
Drulyte, Ieva
Pelzing, Matthias
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Keywords hereditary angioedema
βFXIIa
antigen-antibody complex
HDX-MS
paratope
cryo-EM
garadacimab
C1 esterase inhibitor
epitope mapping
Language English
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Snippet Activated FXII (FXIIa) is the principal initiator of the plasma contact system and can activate both procoagulant and proinflammatory pathways. Its activity is...
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SubjectTerms antigen-antibody complex
C1 esterase inhibitor
cryo-EM
epitope mapping
garadacimab
HDX-MS
hereditary angioedema
paratope
βFXIIa
Title Structural basis for the inhibition of βFXIIa by garadacimab
URI https://dx.doi.org/10.1016/j.str.2024.07.001
https://www.ncbi.nlm.nih.gov/pubmed/39059382
https://www.proquest.com/docview/3085114062
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