View source for 5ar3


==RIP2 Kinase Catalytic Domain (1 - 310) complex with AMP-PCP==
<StructureSection load='5ar3' size='340' side='right'caption='[[5ar3]], [[Resolution|resolution]] 3.23&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[5ar3]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5AR3 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5AR3 FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ACP:PHOSPHOMETHYLPHOSPHONIC+ACID+ADENYLATE+ESTER'>ACP</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5ar2|5ar2]], [[5ar4|5ar4]], [[5ar5|5ar5]], [[5ar7|5ar7]], [[5ar8|5ar8]]</td></tr>
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Non-specific_serine/threonine_protein_kinase Non-specific serine/threonine protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.1 2.7.11.1] </span></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5ar3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ar3 OCA], [http://pdbe.org/5ar3 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5ar3 RCSB], [http://www.ebi.ac.uk/pdbsum/5ar3 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5ar3 ProSAT]</span></td></tr>
</table>
== Function ==
[[http://www.uniprot.org/uniprot/RIPK2_HUMAN RIPK2_HUMAN]] Serine/threonine/tyrosine kinase that plays an essential role in modulation of innate and adaptive immune responses. Upon stimulation by bacterial peptidoglycans, NOD1 and NOD2 are activated, oligomerize and recruit RIPK2 through CARD-CARD domains. Once recruited, RIPK2 autophosphorylates and undergoes 'Lys-63'-linked polyubiquitination by E3 ubiquitin ligases BIRC2 and BIRC3. The polyubiquitinated protein mediates the recruitment of MAP3K7/TAK1 to IKBKG/NEMO and induces 'Lys-63'-linked polyubiquitination of IKBKG/NEMO and subsequent activation of IKBKB/IKKB. In turn, NF-kappa-B is released from NF-kappa-B inhibitors and translocates into the nucleus where it activates the transcription of hundreds of genes involved in immune response, growth control, or protection against apoptosis. Plays also a role during engagement of the T-cell receptor (TCR) in promoting BCL10 phosphorylation and subsequent NF-kappa-B activation.<ref>PMID:14638696</ref> <ref>PMID:17054981</ref> <ref>PMID:18079694</ref> <ref>PMID:21123652</ref>  
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
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 (beta,gamma-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.

Crystal structures of human RIP2 kinase catalytic domain complexed with ATP-competitive inhibitors: Foundations for understanding inhibitor selectivity.,Charnley AK, Convery MA, Lakdawala Shah A, Jones E, Hardwicke P, Bridges A, Ouellette M, Totoritis R, Schwartz B, King BW, Wisnoski DD, Kang J, Eidam PM, Votta BJ, Gough PJ, Marquis RW, Bertin J, Casillas L Bioorg Med Chem. 2015 Sep 25. pii: S0968-0896(15)30063-8. doi:, 10.1016/j.bmc.2015.09.038. PMID:26455654<ref>PMID:26455654</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 5ar3" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Human]]
[[Category: Large Structures]]
[[Category: Non-specific serine/threonine protein kinase]]
[[Category: Bertin, J]]
[[Category: Bridges, A]]
[[Category: Casillas, L]]
[[Category: Charnley, A K]]
[[Category: Convery, M A]]
[[Category: Gough, P J]]
[[Category: Hardwicke, P]]
[[Category: Jones, E]]
[[Category: Marquis, R W]]
[[Category: Shah, A Lakdawala]]
[[Category: Votta, B J]]
[[Category: Inhibitor selectivity]]
[[Category: Kinase inhibitor]]
[[Category: Structure-based drug design]]
[[Category: Transferase]]