PDBsum entry 5ar5

Transferase

PDB id: 5ar5

Contents

Protein chains

284 a.a.

Ligands

IQ7 ×2

Metals

_CA

Waters ×272

PDB id:

5ar5

Name:

Transferase

Title:

Rip2 kinase catalytic domain (1 - 310) complex with benzimidazole

Structure:

Receptor-interacting serine/threonine-protein kinase 2. Chain: a, b. Fragment: kinase domain, unp residues 1-310. Synonym: card-containing interleukin-1 beta-converting enzyme- associated kinase, card-containing il-1 beta ice-kinase, rip-like- interacting clarp kinase, receptor-interacting protein 2, rip-2, tyrosine-protein kinase ripk2. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108.

Resolution:

2.66Å R-factor: 0.172 R-free: 0.217

Authors:

A.K.Charnley,M.A.Convery,A.Lakdawala Shah,E.Jones,P.Hardwicke, A.Bridges,B.J.Votta,P.J.Gough,R.W.Marquis,J.Bertin,L.Casillas

Key ref:

A.K.Charnley et al. (2015). Crystal structures of human RIP2 kinase catalytic domain complexed with ATP-competitive inhibitors: Foundations for understanding inhibitor selectivity. Bioorg Med Chem Lett, 23, 7000-7006. PubMed id: 26455654 DOI: 10.1016/j.bmc.2015.09.038

Date:

24-Sep-15 Release date: 21-Oct-15

Protein chains

O43353  (RIPK2_HUMAN) -  Receptor-interacting serine/threonine-protein kinase 2 from Homo sapiens

Seq: 540 a.a.

Struc: 284 a.a.

Enzyme reactions

• Enzyme class 2: E.C.2.7.10.2 - non-specific protein-tyrosine kinase.
• Reaction: L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H⁺
• Enzyme class 3: E.C.2.7.11.1 - non-specific serine/threonine protein kinase.
• Reaction:
  1. L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H⁺
  2. L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H⁺

Note, where more than one E.C. class is given (as above), each may correspond to a different protein domain or, in the case of polyprotein precursors, to a different mature protein.

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

DOI no: 10.1016/j.bmc.2015.09.038

Bioorg Med Chem Lett 23:7000-7006 (2015)

PubMed id: 26455654

Crystal structures of human RIP2 kinase catalytic domain complexed with ATP-competitive inhibitors: Foundations for understanding inhibitor selectivity.

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.

ABSTRACT

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.