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'''Unreleased structure'''


The entry 6xn9 is ON HOLD
==Solution NMR structure of recifin, a cysteine-rich tyrosyl-DNA Phosphodiesterase I modulatory peptide from the marine sponge Axinella sp.==
<StructureSection load='6xn9' size='340' side='right'caption='[[6xn9]]' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6XN9 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6XN9 FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Solution NMR, 20 models</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=PCA:PYROGLUTAMIC+ACID'>PCA</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=6xn9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6xn9 OCA], [https://pdbe.org/6xn9 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6xn9 RCSB], [https://www.ebi.ac.uk/pdbsum/6xn9 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6xn9 ProSAT]</span></td></tr>
</table>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Tyrosyl-DNA phosphodiesterase 1 (TDP1) is a molecular target for the sensitization of cancer cells to the FDA-approved topoisomerase inhibitors topotecan and irinotecan. High-throughput screening of natural product extract and fraction libraries for inhibitors of TDP1 activity resulted in the discovery of a new class of knotted cyclic peptides from the marine sponge Axinella sp. Bioassay-guided fractionation of the source extract resulted in the isolation of the active component which was determined to be an unprecedented 42-residue cysteine-rich peptide named recifin A. The native NMR structure revealed a novel fold comprising a four strand antiparallel beta-sheet and two helical turns stabilized by a complex disulfide bond network that creates an embedded ring around one of the strands. The resulting structure, which we have termed the Tyr-lock peptide family, is stabilized by a tyrosine residue locked into three-dimensional space. Recifin A inhibited the cleavage of phosphodiester bonds by TDP1 in a FRET assay with an IC50 of 190 nM. Enzyme kinetics studies revealed that recifin A can specifically modulate the enzymatic activity of full-length TDP1 while not affecting the activity of a truncated catalytic domain of TDP1 lacking the N-terminal regulatory domain (Delta1-147), suggesting an allosteric binding site for recifin A on the regulatory domain of TDP1. Recifin A represents both the first of a unique structural class of knotted disulfide-rich peptides and defines a previously unseen mechanism of TDP1 inhibition that could be productively exploited for potential anticancer applications.


Authors: Schroeder, C.I., Rosengren, K.J., O'Keefe, B.R.
Recifin A, Initial Example of the Tyr-Lock Peptide Structural Family, Is a Selective Allosteric Inhibitor of Tyrosyl-DNA Phosphodiesterase I.,Krumpe LRH, Wilson BAP, Marchand C, Sunassee SN, Bermingham A, Wang W, Price E, Guszczynski T, Kelley JA, Gustafson KR, Pommier Y, Rosengren KJ, Schroeder CI, O'Keefe BR J Am Chem Soc. 2020 Dec 16;142(50):21178-21188. doi: 10.1021/jacs.0c10418. Epub, 2020 Dec 2. PMID:33263997<ref>PMID:33263997</ref>


Description: Solution NMR structure of recifin, a cysteine-rich tyrosyl-DNA Phosphodiesterase I modulatory peptide from the marine sponge Axinella sp.
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
[[Category: Unreleased Structures]]
</div>
[[Category: Rosengren, K.J]]
<div class="pdbe-citations 6xn9" style="background-color:#fffaf0;"></div>
[[Category: Schroeder, C.I]]
== References ==
[[Category: O'Keefe, B.R]]
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: O'Keefe BR]]
[[Category: Rosengren KJ]]
[[Category: Schroeder CI]]
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