View source for 9fl8


==Stapled peptide bound to NOT9-NOT1 complex==
<StructureSection load='9fl8' size='340' side='right'caption='[[9fl8]], [[Resolution|resolution]] 2.64&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[9fl8]] is a 6 chain structure with sequence from [https://en.wikipedia.org/wiki/Drosophila_melanogaster Drosophila melanogaster] and [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=9FL8 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9FL8 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]] 2.64&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACE:ACETYL+GROUP'>ACE</scene>, <scene name='pdbligand=BU1:1,4-BUTANEDIOL'>BU1</scene>, <scene name='pdbligand=MK8:2-METHYL-L-NORLEUCINE'>MK8</scene>, <scene name='pdbligand=NH2:AMINO+GROUP'>NH2</scene>, <scene name='pdbligand=NLE:NORLEUCINE'>NLE</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=9fl8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9fl8 OCA], [https://pdbe.org/9fl8 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9fl8 RCSB], [https://www.ebi.ac.uk/pdbsum/9fl8 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9fl8 ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/BAM_DROME BAM_DROME] Required to initiate both male and female gametogenesis. May regulate cystoblast cell divisions.<ref>PMID:2279698</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Therapeutic intervention targeting mRNA typically aims at reducing the levels of disease-causing sequences. Achieving the opposite effect of blocking the destruction of beneficial mRNA remains underexplored. The degradation of mRNA starts with the removal of poly(A) tails, reducing their stability and translational activity, which is mainly regulated by the CCR4-NOT complex. The subunit NOT9 binds various RNA binding proteins, that recruit mRNA in a sequence-specific manner to the CCR4-NOT complex to promote their deadenylation. These RNA binding proteins interact with NOT9 through a helical NOT9 binding motif, which we used as a starting point for development of the hydrocarbon stapled peptide NIP-2. The peptide (K(D)=60.4 nM) was able to inhibit RNA-binding (IC(50)=333 nM) as well as the deadenylation activity of the CCR4-NOT complex in vitro while being cell-permeable (cell-permeability EC(50)=2.44 muM). A co-crystal structure of NIP-2 bound to NOT9 allowed further optimization of the peptide through point mutation leading to NIP-2-H27A-N(3) (K(D)=122 nM) with high cell permeability (cell-permeability EC(50)=0.34 muM). The optimized peptide was able to inhibit deadenylation of target mRNAs when used in HeLa cells at a concentration of 100 muM, demonstrating the feasibility of increasing mRNA stability.

Stapled Peptides as Inhibitors of mRNA Deadenylation.,Pal S, Gordijenko I, Schmeing S, Biswas S, Akbulut Y, Gasper R, 't Hart P Angew Chem Int Ed Engl. 2025 Jan 2;64(1):e202413911. doi: 10.1002/anie.202413911. , Epub 2024 Nov 6. PMID:39319385<ref>PMID:39319385</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 9fl8" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Drosophila melanogaster]]
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Gasper R]]
[[Category: Pal S]]
[[Category: Schmeing S]]
[[Category: T Hart P]]