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PDBsum entry 5alc
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Immune system
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PDB id
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5alc
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PDB id:
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Immune system
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Title:
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Ticagrelor antidote candidate fab 72 in complex with ticagrelor
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Structure:
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Anti-ticagrelor fab 72, heavy chain. Chain: h. Engineered: yes. Anti-ticagrelor fab 72, light chain. Chain: l. Engineered: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Expressed in: cricetulus griseus. Expression_system_taxid: 10029. Expression_system_cell_line: cho-k1. Expression_system_cell_line: cho-k1
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Resolution:
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1.70Å
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R-factor:
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0.200
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R-free:
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0.237
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Authors:
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A.Buchanan,P.Newton,S.Pehrsson,T.Inghardt,T.Antonsson,P.Svensson, T.Sjogren,L.Oster,A.Janefeldt,A.Sandinge,F.Keyes,M.Austin,J.Spooner, M.Penney,G.Howells,T.Vaughan,S.Nylander
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Key ref:
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A.Buchanan
et al.
(2015).
Structural and functional characterization of a specific antidote for ticagrelor.
Blood,
125,
3484-3490.
PubMed id:
DOI:
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Date:
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07-Mar-15
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Release date:
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01-Apr-15
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PROCHECK
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Headers
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References
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DOI no:
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Blood
125:3484-3490
(2015)
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PubMed id:
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Structural and functional characterization of a specific antidote for ticagrelor.
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A.Buchanan,
P.Newton,
S.Pehrsson,
T.Inghardt,
T.Antonsson,
P.Svensson,
T.Sjögren,
L.Öster,
A.Janefeldt,
A.S.Sandinge,
F.Keyes,
M.Austin,
J.Spooner,
P.Gennemark,
M.Penney,
G.Howells,
T.Vaughan,
S.Nylander.
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ABSTRACT
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Ticagrelor is a direct-acting reversibly binding P2Y12 antagonist and is widely
used as an antiplatelet therapy for the prevention of cardiovascular events in
acute coronary syndrome patients. However, antiplatelet therapy can be
associated with an increased risk of bleeding. Here, we present data on the
identification and the in vitro and in vivo pharmacology of an antigen-binding
fragment (Fab) antidote for ticagrelor. The Fab has a 20 pM affinity for
ticagrelor, which is 100 times stronger than ticagrelor's affinity for its
target, P2Y12. Despite ticagrelor's structural similarities to adenosine, the
Fab is highly specific and does not bind to adenosine, adenosine triphosphate,
adenosine 5'-diphosphate, or structurally related drugs. The antidote
concentration-dependently neutralized the free fraction of ticagrelor and
reversed its antiplatelet activity both in vitro in human platelet-rich plasma
and in vivo in mice. Lastly, the antidote proved effective in normalizing
ticagrelor-dependent bleeding in a mouse model of acute surgery. This specific
antidote for ticagrelor may prove valuable as an agent for patients who require
emergency procedures.
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Links
