View source for 11zl


==Crystal Structure of human JNK1 Kinase Domain in complex with inhibitor CCD-3013==
<StructureSection load='11zl' size='340' side='right'caption='[[11zl]], [[Resolution|resolution]] 1.55&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[11zl]] is a 1 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=11ZL OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=11ZL 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]] 1.55&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1DA9:(4M)-N-[4-hydroxy-3-(pyrrolidine-1-carbonyl)phenyl]-4-(1H-pyrrolo[2,3-b]pyridin-5-yl)-1-benzothiophene-2-carboxamide'>A1DA9</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=11zl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=11zl OCA], [https://pdbe.org/11zl PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=11zl RCSB], [https://www.ebi.ac.uk/pdbsum/11zl PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=11zl ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/MK08_HUMAN MK08_HUMAN] Serine/threonine-protein kinase involved in various processes such as cell proliferation, differentiation, migration, transformation and programmed cell death. Extracellular stimuli such as proinflammatory cytokines or physical stress stimulate the stress-activated protein kinase/c-Jun N-terminal kinase (SAP/JNK) signaling pathway. In this cascade, two dual specificity kinases MAP2K4/MKK4 and MAP2K7/MKK7 phosphorylate and activate MAPK8/JNK1. In turn, MAPK8/JNK1 phosphorylates a number of transcription factors, primarily components of AP-1 such as JUN, JDP2 and ATF2 and thus regulates AP-1 transcriptional activity. Phosphorylates the replication licensing factor CDT1, inhibiting the interaction between CDT1 and the histone H4 acetylase HBO1 to replication origins. Loss of this interaction abrogates the acetylation required for replication initiation. Promotes stressed cell apoptosis by phosphorylating key regulatory factors including p53/TP53 and Yes-associates protein YAP1. In T-cells, MAPK8 and MAPK9 are required for polarized differentiation of T-helper cells into Th1 cells. Contributes to the survival of erythroid cells by phosphorylating the antagonist of cell death BAD upon EPO stimulation. Mediates starvation-induced BCL2 phosphorylation, BCL2 dissociation from BECN1, and thus activation of autophagy. Phosphorylates STMN2 and hence regulates microtubule dynamics, controlling neurite elongation in cortical neurons. In the developing brain, through its cytoplasmic activity on STMN2, negatively regulates the rate of exit from multipolar stage and of radial migration from the ventricular zone. Phosphorylates several other substrates including heat shock factor protein 4 (HSF4), the deacetylase SIRT1, ELK1, or the E3 ligase ITCH.<ref>PMID:16581800</ref> <ref>PMID:17296730</ref> <ref>PMID:18307971</ref> <ref>PMID:18570871</ref> <ref>PMID:20027304</ref> <ref>PMID:21364637</ref> <ref>PMID:21095239</ref> <ref>PMID:21856198</ref>   JNK1 isoforms display different binding patterns: beta-1 preferentially binds to c-Jun, whereas alpha-1, alpha-2, and beta-2 have a similar low level of binding to both c-Jun or ATF2. However, there is no correlation between binding and phosphorylation, which is achieved at about the same efficiency by all isoforms.<ref>PMID:16581800</ref> <ref>PMID:17296730</ref> <ref>PMID:18307971</ref> <ref>PMID:18570871</ref> <ref>PMID:20027304</ref> <ref>PMID:21364637</ref> <ref>PMID:21095239</ref> <ref>PMID:21856198</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Endometriosis, defined as the ectopic growth of endometrial tissue outside of the uterine cavity, is an inflammatory and hormone-dependent disease that causes excruciating pelvic pain, infertility, and significantly decreases quality of life in affected patients. The JUN N-terminal kinases (JNKs) are a leading class of nonhormonal therapeutic targets that have been validated in preclinical models of endometriosis and in a Phase 1/2 clinical trial. Despite their therapeutic potential, JNK inhibitors with increased potency and specificity are needed to address the inflammatory pathology of endometriosis and to prevent disease progression. Leveraging a DNA-encoded chemical library collection of ~4 billion compounds, we identified lead inhibitor CDD-2428 and optimized derivatives, CDD-2728 and CDD-3013, with excellent binding affinity to JNK1-3 (K(d) = 0.12 to 3.7 nM), enhanced selectivity, metabolic stability, and cellular permeability. Crystallographic and biochemical studies confirmed that CDD-3013 exhibited superior kinase selectivity with improved efficacy compared to existing JNK inhibitors. In primary endometriosis cell models, CDD-2728 and CDD-3013 suppressed JNK-dependent inflammatory signaling, dampening pathways linked to pain, invasion, angiogenesis, and macrophage recruitment. In an endometriosis mouse model, both CDD-2728 and CDD-3013 reduced endometriotic lesion size, macrophage infiltration, and cellular proliferation, showing in vivo efficacy. When tested in a lipopolysaccharide-induced hyperalgesia model, CDD-2728 and CDD-3013 decreased markers of induced pain, as measured by changes in a dynamic weight bearing test and Grimace scores. These findings nominate CDD-2728 and CDD-3013 as potent, nonhormonal therapeutic candidates for endometriosis with broad anti-inflammatory and analgesic activity, addressing a critical unmet clinical need.

Identification of potent inhibitors of JUN N-terminal kinases for treatment of endometriosis and associated pain.,Madasu C, Sirupangi T, Herrera GJ, Bohren KM, Sharma KL, Tan Z, Ta HM, Yuan F, Palaniappan M, Clementi C, Tang S, Unser AC, Wilkinson J, Robers MB, Guan X, Li F, Kim C, Sankaran B, Kommagani R, Chamakuri S, Young DW, Biem PY, Matzuk MM, Palmer SS, Monsivais D Proc Natl Acad Sci U S A. 2026 Aug 25;123(34):e2607561123. doi: , 10.1073/pnas.2607561123. Epub 2026 Aug 19. PMID:42616792<ref>PMID:42616792</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 11zl" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Kim C]]
[[Category: Madasu C]]
[[Category: Matzuk MM]]
[[Category: Monsivais D]]
[[Category: Palmer SS]]
[[Category: Sirupangi T]]
[[Category: Ta HM]]