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==TNNI3K complexed with inhibitor 1==
==TNNI3K complexed with inhibitor 1==
<StructureSection load='4yfi' size='340' side='right' caption='[[4yfi]], [[Resolution|resolution]] 2.70&Aring;' scene=''>
<StructureSection load='4yfi' size='340' side='right'caption='[[4yfi]], [[Resolution|resolution]] 2.70&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[4yfi]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4YFI OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4YFI FirstGlance]. <br>
<table><tr><td colspan='2'>[[4yfi]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4YFI OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4YFI FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=4CW:N-METHYL-3-(9H-PURIN-6-YLAMINO)BENZENESULFONAMIDE'>4CW</scene></td></tr>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.7&#8491;</td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4yff|4yff]]</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=4CW:N-METHYL-3-(9H-PURIN-6-YLAMINO)BENZENESULFONAMIDE'>4CW</scene></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'>[https://proteopedia.org/fgij/fg.htm?mol=4yfi FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4yfi OCA], [https://pdbe.org/4yfi PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4yfi RCSB], [https://www.ebi.ac.uk/pdbsum/4yfi PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4yfi ProSAT]</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=4yfi FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4yfi OCA], [http://pdbe.org/4yfi PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4yfi RCSB], [http://www.ebi.ac.uk/pdbsum/4yfi PDBsum]</span></td></tr>
</table>
</table>
== Disease ==
== Disease ==
[[http://www.uniprot.org/uniprot/TNI3K_HUMAN TNI3K_HUMAN]] The disease is caused by mutations affecting the gene represented in this entry.  
[https://www.uniprot.org/uniprot/TNI3K_HUMAN TNI3K_HUMAN] The disease is caused by mutations affecting the gene represented in this entry.
== Function ==
== Function ==
[[http://www.uniprot.org/uniprot/TNI3K_HUMAN TNI3K_HUMAN]] May play a role in cardiac physiology.<ref>PMID:12721663</ref> 
[https://www.uniprot.org/uniprot/TNI3K_HUMAN TNI3K_HUMAN] May play a role in cardiac physiology.<ref>PMID:12721663</ref>  
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
A series of cardiac troponin I-interacting kinase (TNNI3K) inhibitors arising from 3-((9H-purin-6-yl)amino)-N-methyl-benzenesulfonamide (1) is disclosed along with fundamental structure-function relationships that delineate the role of each element of 1 for TNNI3K recognition. An X-ray structure of 1 bound to TNNI3K confirmed its Type I binding mode and is used to rationalize the structure-activity relationship and employed to design potent, selective, and orally bioavailable TNNI3K inhibitors. Identification of the 7-deazapurine heterocycle as a superior template (vs purine) and its elaboration by introduction of C4-benzenesulfonamide and C7- and C8-7-deazapurine substituents produced compounds with substantial improvements in potency (&gt;1000-fold), general kinase selectivity (10-fold improvement), and pharmacokinetic properties (&gt;10-fold increase in poDNAUC). Optimal members of the series have properties suitable for use in in vitro and in vivo experiments aimed at elucidating the role of TNNI3K in cardiac biology and serve as leads for developing novel heart failure medicines.
 
Identification of Purines and 7-Deazapurines as Potent and Selective Type I Inhibitors of Troponin I-Interacting Kinase (TNNI3K).,Lawhorn BG, Philp J, Zhao Y, Louer C, Hammond M, Cheung M, Fries H, Graves AP, Shewchuk L, Wang L, Cottom JE, Qi H, Zhao H, Totoritis R, Zhang G, Schwartz B, Li H, Sweitzer S, Holt DA, Gatto GJ Jr, Kallander LS J Med Chem. 2015 Sep 24;58(18):7431-48. doi: 10.1021/acs.jmedchem.5b00931. Epub, 2015 Sep 10. PMID:26355916<ref>PMID:26355916</ref>


From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
==See Also==
</div>
*[[Serine/threonine protein kinase 3D structures|Serine/threonine protein kinase 3D structures]]
<div class="pdbe-citations 4yfi" style="background-color:#fffaf0;"></div>
== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Non-specific serine/threonine protein kinase]]
[[Category: Homo sapiens]]
[[Category: Lawhorn, B G]]
[[Category: Large Structures]]
[[Category: Shewchuk, L M]]
[[Category: Lawhorn BG]]
[[Category: Wang, L]]
[[Category: Shewchuk LM]]
[[Category: Kinase]]
[[Category: Wang L]]
[[Category: Transferase-transferase inhibitor complex]]

Latest revision as of 16:03, 1 March 2024

TNNI3K complexed with inhibitor 1TNNI3K complexed with inhibitor 1

Structural highlights

4yfi is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.7Å
Ligands:
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

TNI3K_HUMAN The disease is caused by mutations affecting the gene represented in this entry.

Function

TNI3K_HUMAN May play a role in cardiac physiology.[1]

See Also

References

  1. ↑ Zhao Y, Meng XM, Wei YJ, Zhao XW, Liu DQ, Cao HQ, Liew CC, Ding JF. Cloning and characterization of a novel cardiac-specific kinase that interacts specifically with cardiac troponin I. J Mol Med. 2003 May;81(5):297-304. Epub 2003 Apr 30. PMID:12721663 doi:http://dx.doi.org/10.1007/s00109-003-0427-x

4yfi, resolution 2.70Å

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