View source for 9mzx


==Crystal structure of human RIPK1 with Compound 1==
<StructureSection load='9mzx' size='340' side='right'caption='[[9mzx]], [[Resolution|resolution]] 2.53&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[9mzx]] is a 2 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=9MZX OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9MZX FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.53&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1BU4:1-[(2S,5S)-2,3-dihydro-2,5-methano-1,4-benzoxazepin-4(5H)-yl]-2,2-dimethylpropan-1-one'>A1BU4</scene>, <scene name='pdbligand=IOD:IODIDE+ION'>IOD</scene></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=9mzx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9mzx OCA], [https://pdbe.org/9mzx PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9mzx RCSB], [https://www.ebi.ac.uk/pdbsum/9mzx PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9mzx ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/RIPK1_HUMAN RIPK1_HUMAN] Serine-threonine kinase which transduces inflammatory and cell-death signals (programmed necrosis) following death receptors ligation, activation of pathogen recognition receptors (PRRs), and DNA damage. Upon activation of TNFR1 by the TNF-alpha family cytokines, TRADD and TRAF2 are recruited to the receptor. Ubiquitination by TRAF2 via 'Lys-63'-link chains acts as a critical enhancer of communication with downstream signal transducers in the mitogen-activated protein kinase pathway and the NF-kappa-B pathway, which in turn mediate downstream events including the activation of genes encoding inflammatory molecules. Polyubiquitinated protein binds to IKBKG/NEMO, the regulatory subunit of the IKK complex, a critical event for NF-kappa-B activation. Interaction with other cellular RHIM-containing adapters initiates gene activation and cell death. RIPK1 and RIPK3 association, in particular, forms a necrosis-inducing complex.<ref>PMID:11101870</ref> <ref>PMID:19524513</ref> <ref>PMID:19524512</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Receptor-interacting protein kinase 1 (RIPK1) plays an essential role in necroptosis, a form of inflammatory, caspase-independent, programmed cell death. Allosteric inhibitors of RIPK1 have been shown to block necroptotic cell death and thus may offer potential therapeutic opportunities across a range of infectious, autoimmune, and neurodegenerative diseases. We report the structure-informed discovery of a novel series of bridged benzoazepine amides as part of our efforts to develop a CNS-penetrant small-molecule inhibitor of RIPK1 with a low projected oral human dose.

The Discovery of Bridged Benzoazepine Amides as Selective Allosteric Modulators of RIPK1.,Chen JL, Methot JL, Mitcheltree MJ, Musacchio A, Corcoran EB, Feng G, Lammens A, Maskos K, Palte RL, Rickard MM, Otte KM, Mansueto MS, Venkat S, Sondey C, Thomsen M, Lesburg CA, Fradera X, Fell MJ, DiMauro EF, Siliphaivanh P ACS Med Chem Lett. 2025 Apr 14;16(5):811-818. doi: , 10.1021/acsmedchemlett.5c00063. eCollection 2025 May 8. PMID:40365380<ref>PMID:40365380</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 9mzx" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Lammens A]]
[[Category: Lesburg CA]]
[[Category: Maskos K]]
[[Category: Palte RL]]
[[Category: Thomsen M]]