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{{STRUCTURE_4i0s|  PDB=4i0s  |  SCENE=  }}
==Crystal structure of spleen tyrosine kinase complexed with 2-(6-Chloro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid isopropylamide==
===Crystal structure of spleen tyrosine kinase complexed with 2-(6-Chloro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid isopropylamide===
<StructureSection load='4i0s' size='340' side='right' caption='[[4i0s]], [[Resolution|resolution]] 1.98&Aring;' scene=''>
{{ABSTRACT_PUBMED_23350847}}
== Structural highlights ==
<table><tr><td colspan='2'>[[4i0s]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4I0S OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4I0S FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=1B5:2-(6-CHLORO-1-METHYL-1H-INDAZOL-3-YL)-N-(PROPAN-2-YL)-5H-PYRROLO[2,3-B]PYRAZINE-7-CARBOXAMIDE'>1B5</scene></td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4i0r|4i0r]], [[4i0t|4i0t]]</td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">SYK ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</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_protein-tyrosine_kinase Non-specific protein-tyrosine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.2 2.7.10.2] </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=4i0s FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4i0s OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4i0s RCSB], [http://www.ebi.ac.uk/pdbsum/4i0s PDBsum]</span></td></tr>
</table>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
We describe the discovery of several pyrrolopyrazines as potent and selective Syk inhibitors and the efforts that eventually led to the desired improvements in physicochemical properties and human whole blood potencies. Ultimately, our mouse model revealed unexpected toxicity that precluded us from further advancing this series.


==Function==
Pyrrolopyrazines as selective spleen tyrosine kinase inhibitors.,Padilla F, Bhagirath N, Chen S, Chiao E, Goldstein DM, Hermann JC, Hsu J, Kennedy-Smith JJ, Kuglstatter A, Liao C, Liu W, Lowrie LE Jr, Luk KC, Lynch SM, Menke J, Niu L, Owens TD, O-Yang C, Railkar A, Schoenfeld RC, Slade M, Steiner S, Tan YC, Villasenor AG, Wang C, Wanner J, Xie W, Xu D, Zhang X, Zhou M, Lucas MC J Med Chem. 2013 Feb 28;56(4):1677-92. doi: 10.1021/jm301720p. Epub 2013 Feb 12. PMID:23350847<ref>PMID:23350847</ref>
[[http://www.uniprot.org/uniprot/KSYK_HUMAN KSYK_HUMAN]] Non-receptor tyrosine kinase which mediates signal transduction downstream of a variety of transmembrane receptors including classical immunoreceptors like the B-cell receptor (BCR). Regulates several biological processes including innate and adaptive immunity, cell adhesion, osteoclast maturation, platelet activation and vascular development. Assembles into signaling complexes with activated receptors at the plasma membrane via interaction between its SH2 domains and the receptor tyrosine-phosphorylated ITAM domains. The association with the receptor can also be indirect and mediated by adapter proteins containing ITAM or partial hemITAM domains. The phosphorylation of the ITAM domains is generally mediated by SRC subfamily kinases upon engagement of the receptor. More rarely signal transduction via SYK could be ITAM-independent. Direct downstream effectors phosphorylated by SYK include VAV1, PLCG1, PI-3-kinase, LCP2 and BLNK. Initially identified as essential in B-cell receptor (BCR) signaling, it is necessary for the maturation of B-cells most probably at the pro-B to pre-B transition. Activated upon BCR engagement, it phosphorylates and activates BLNK an adapter linking the activated BCR to downstream signaling adapters and effectors. It also phosphorylates and activates PLCG1 and the PKC signaling pathway. It also phosphorylates BTK and regulates its activity in B-cell antigen receptor (BCR)-coupled signaling. Beside its function downstream of BCR plays also a role in T-cell receptor signaling. Plays also a crucial role in the innate immune response to fungal, bacterial and viral pathogens. It is for instance activated by the membrane lectin CLEC7A. Upon stimulation by fungal proteins, CLEC7A together with SYK activates immune cells inducing the production of ROS. Also activates the inflammasome and NF-kappa-B-mediated transcription of chemokines and cytokines in presence of pathogens. Regulates neutrophil degranulation and phagocytosis through activation of the MAPK signaling cascade. Also mediates the activation of dendritic cells by cell necrosis stimuli. Also involved in mast cells activation. Also functions downstream of receptors mediating cell adhesion. Relays for instance, integrin-mediated neutrophils and macrophages activation and P-selectin receptor/SELPG-mediated recruitment of leukocytes to inflammatory loci. Plays also a role in non-immune processes. It is for instance involved in vascular development where it may regulate blood and lymphatic vascular separation. It is also required for osteoclast development and function. Functions in the activation of platelets by collagen, mediating PLCG2 phosphorylation and activation. May be coupled to the collagen receptor by the ITAM domain-containing FCER1G. Also activated by the membrane lectin CLEC1B that is required for activation of platelets by PDPN/podoplanin. Involved in platelet adhesion being activated by ITGB3 engaged by fibrinogen.<ref>PMID:8657103</ref> <ref>PMID:9535867</ref> <ref>PMID:12456653</ref> <ref>PMID:12387735</ref> <ref>PMID:15388330</ref> <ref>PMID:19909739</ref>


==About this Structure==
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
[[4i0s]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4I0S OCA].
</div>


==Reference==
==See Also==
<ref group="xtra">PMID:023350847</ref><references group="xtra"/><references/>
*[[Tyrosine kinase|Tyrosine kinase]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Non-specific protein-tyrosine kinase]]
[[Category: Non-specific protein-tyrosine kinase]]
[[Category: Kuglstatter, A.]]
[[Category: Kuglstatter, A]]
[[Category: Slade, M.]]
[[Category: Slade, M]]
[[Category: Kinase inhibitor]]
[[Category: Kinase inhibitor]]
[[Category: Transferase-transferase inhibitor complex]]
[[Category: Transferase-transferase inhibitor complex]]

Revision as of 15:37, 21 December 2014

Crystal structure of spleen tyrosine kinase complexed with 2-(6-Chloro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid isopropylamideCrystal structure of spleen tyrosine kinase complexed with 2-(6-Chloro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid isopropylamide

Structural highlights

4i0s is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Gene:SYK (Homo sapiens)
Activity:Non-specific protein-tyrosine kinase, with EC number 2.7.10.2
Resources:FirstGlance, OCA, RCSB, PDBsum

Publication Abstract from PubMed

We describe the discovery of several pyrrolopyrazines as potent and selective Syk inhibitors and the efforts that eventually led to the desired improvements in physicochemical properties and human whole blood potencies. Ultimately, our mouse model revealed unexpected toxicity that precluded us from further advancing this series.

Pyrrolopyrazines as selective spleen tyrosine kinase inhibitors.,Padilla F, Bhagirath N, Chen S, Chiao E, Goldstein DM, Hermann JC, Hsu J, Kennedy-Smith JJ, Kuglstatter A, Liao C, Liu W, Lowrie LE Jr, Luk KC, Lynch SM, Menke J, Niu L, Owens TD, O-Yang C, Railkar A, Schoenfeld RC, Slade M, Steiner S, Tan YC, Villasenor AG, Wang C, Wanner J, Xie W, Xu D, Zhang X, Zhou M, Lucas MC J Med Chem. 2013 Feb 28;56(4):1677-92. doi: 10.1021/jm301720p. Epub 2013 Feb 12. PMID:23350847[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

See Also

References

  1. ↑ Padilla F, Bhagirath N, Chen S, Chiao E, Goldstein DM, Hermann JC, Hsu J, Kennedy-Smith JJ, Kuglstatter A, Liao C, Liu W, Lowrie LE Jr, Luk KC, Lynch SM, Menke J, Niu L, Owens TD, O-Yang C, Railkar A, Schoenfeld RC, Slade M, Steiner S, Tan YC, Villasenor AG, Wang C, Wanner J, Xie W, Xu D, Zhang X, Zhou M, Lucas MC. Pyrrolopyrazines as selective spleen tyrosine kinase inhibitors. J Med Chem. 2013 Feb 28;56(4):1677-92. doi: 10.1021/jm301720p. Epub 2013 Feb 12. PMID:23350847 doi:http://dx.doi.org/10.1021/jm301720p

4i0s, resolution 1.98Å

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