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PDBsum entry 5ar7
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References listed in PDB file
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Key reference
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Title
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Crystal structures of human rip2 kinase catalytic domain complexed with ATP-Competitive inhibitors: foundations for understanding inhibitor selectivity.
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Authors
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A.K.Charnley,
M.A.Convery,
A.Lakdawala shah,
E.Jones,
P.Hardwicke,
A.Bridges,
M.Ouellette,
R.Totoritis,
B.Schwartz,
B.W.King,
D.D.Wisnoski,
J.Kang,
P.M.Eidam,
B.J.Votta,
P.J.Gough,
R.W.Marquis,
J.Bertin,
L.Casillas.
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Ref.
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Bioorg Med Chem Lett, 2015,
23,
7000-7006.
[DOI no: ]
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PubMed id
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Abstract
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Receptor interacting protein 2 (RIP2) is an intracellular kinase and key
signaling partner for the pattern recognition receptors NOD1 and NOD2
(nucleotide-binding oligomerization domain-containing proteins 1 and 2). As
such, RIP2 represents an attractive target to probe the role of these pathways
in disease. In an effort to design potent and selective inhibitors of RIP2 we
established a crystallographic system and determined the structure of the RIP2
kinase domain in an apo form and also in complex with multiple inhibitors
including AMP-PCP (β,γ-Methyleneadenosine 5'-triphosphate, a non-hydrolysable
adenosine triphosphate mimic) and structurally diverse ATP competitive
chemotypes identified via a high-throughput screening campaign. These structures
represent the first set of diverse RIP2-inhibitor co-crystal structures and
demonstrate that the protein possesses the ability to adopt multiple DFG-in as
well as DFG-out and C-helix out conformations. These structures reveal key
protein-inhibitor structural insights and serve as the foundation for
establishing a robust structure-based drug design effort to identify both potent
and highly selective inhibitors of RIP2 kinase.
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