6s3c: Difference between revisions

Latest revision as of 13:06, 6 November 2024

Fragment AZ-019 binding at the p53pT387/14-3-3 sigma interface

Structural highlights

Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2Å
Ligands:	CL, GOL, KDK, MG, TPO
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Publication Abstract from PubMed

Stabilization of protein-protein interactions (PPIs) holds great potential for therapeutic agents, as illustrated by the successful drugs rapamycin and lenalidomide. However, how such interface-binding molecules can be created in a rational, bottom-up manner is a largely unanswered question. We report here how a fragment-based approach can be used to identify chemical starting points for the development of small-molecule stabilizers that differentiate between two different PPI interfaces of the adapter protein 14-3-3. The fragments discriminately bind to the interface of 14-3-3 with the recognition motif of either the tumor suppressor protein p53 or the oncogenic transcription factor TAZ. This x-ray crystallography driven study shows that the rim of the interface of individual 14-3-3 complexes can be targeted in a differential manner with fragments that represent promising starting points for the development of specific 14-3-3 PPI stabilizers.

Fragment-based Differential Targeting of PPI Stabilizer Interfaces.,Guillory X, Wolter M, Leysen S, Neves JF, Kuusk A, Genet S, Somsen B, Morrow J, Rivers E, van Beek L, Patel J, Goodnow R, Schoenherr H, Fuller N, Cao Q, Doveston RG, Brunsveld L, Arkin MR, Castaldi MP, Boyd H, Landrieu I, Chen H, Ottmann C J Med Chem. 2020 Jun 5. doi: 10.1021/acs.jmedchem.9b01942. PMID:32501690^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Guillory X, Wolter M, Leysen S, Neves JF, Kuusk A, Genet S, Somsen B, Morrow J, Rivers E, van Beek L, Patel J, Goodnow R, Schoenherr H, Fuller N, Cao Q, Doveston RG, Brunsveld L, Arkin MR, Castaldi MP, Boyd H, Landrieu I, Chen H, Ottmann C. Fragment-based Differential Targeting of PPI Stabilizer Interfaces. J Med Chem. 2020 Jun 5. doi: 10.1021/acs.jmedchem.9b01942. PMID:32501690 doi:https://dx.doi.org/10.1021/acs.jmedchem.9b01942

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OCA

[1] Guillory X, Wolter M, Leysen S, Neves JF, Kuusk A, Genet S, Somsen B, Morrow J, Rivers E, van Beek L, Patel J, Goodnow R, Schoenherr H, Fuller N, Cao Q, Doveston RG, Brunsveld L, Arkin MR, Castaldi MP, Boyd H, Landrieu I, Chen H, Ottmann C. Fragment-based Differential Targeting of PPI Stabilizer Interfaces. J Med Chem. 2020 Jun 5. doi: 10.1021/acs.jmedchem.9b01942. PMID:32501690 doi:https://dx.doi.org/10.1021/acs.jmedchem.9b01942

[1]

@@ Line 3: / Line 3: @@
 <StructureSection load='6s3c' size='340' side='right'caption='[[6s3c]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6s3c]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6S3C OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6S3C FirstGlance]. <br>
+<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6S3C OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6S3C FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=KDK:4-phenyl-5-(piperidin-4-ylmethyl)thiophene-2-carboximidamide'>KDK</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</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&#8491;</td></tr>
-<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=TPO:PHOSPHOTHREONINE'>TPO</scene></td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=KDK:4-phenyl-5-(piperidin-4-ylmethyl)thiophene-2-carboximidamide'>KDK</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=TPO:PHOSPHOTHREONINE'>TPO</scene></td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">SFN, HME1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=6s3c FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6s3c OCA], [https://pdbe.org/6s3c PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6s3c RCSB], [https://www.ebi.ac.uk/pdbsum/6s3c PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6s3c ProSAT]</span></td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6s3c FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6s3c OCA], [http://pdbe.org/6s3c PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6s3c RCSB], [http://www.ebi.ac.uk/pdbsum/6s3c PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6s3c ProSAT]</span></td></tr>
 </table>
-== Function ==
-[[http://www.uniprot.org/uniprot/1433S_HUMAN 1433S_HUMAN]] Adapter protein implicated in the regulation of a large spectrum of both general and specialized signaling pathways. Binds to a large number of partners, usually by recognition of a phosphoserine or phosphothreonine motif. Binding generally results in the modulation of the activity of the binding partner. When bound to KRT17, regulates protein synthesis and epithelial cell growth by stimulating Akt/mTOR pathway (By similarity).  p53-regulated inhibitor of G2/M progression.
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 20: / Line 17: @@
 </div>
 <div class="pdbe-citations 6s3c" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[14-3-3 protein 3D structures|14-3-3 protein 3D structures]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
-[[Category: Human]]
 [[Category: Large Structures]]
-[[Category: Castaldi, P]]
+[[Category: Castaldi P]]
-[[Category: Genet, S]]
+[[Category: Genet S]]
-[[Category: Guillory, X]]
+[[Category: Guillory X]]
-[[Category: Leysen, S]]
+[[Category: Leysen S]]
-[[Category: Ottmann, C]]
+[[Category: Ottmann C]]
-[[Category: Somsen, B]]
+[[Category: Somsen B]]
-[[Category: Wolter, M]]
+[[Category: Wolter M]]
-[[Category: Fragment soaking]]
-[[Category: Peptide binding protein]]
-[[Category: Protein protein interaction]]
-[[Category: Stabilization]]

6s3c: Difference between revisions

Latest revision as of 13:06, 6 November 2024

Fragment AZ-019 binding at the p53pT387/14-3-3 sigma interface

Structural highlights

Publication Abstract from PubMed

See Also

References

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