5exa

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Small-molecule stabilization of the 14-3-3/Gab2 PPI interface

Structural highlights

5exa is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.95Å
Ligands:	, ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

1433Z_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.^[1] ^[2] ^[3] ^[4] ^[5]

Publication Abstract from PubMed

Small-molecule modulation of protein-protein interactions (PPIs) is one of the most promising new areas in drug discovery. In the vast majority of cases only inhibition or disruption of PPIs is realized, whereas the complementary strategy of targeted stabilization of PPIs is clearly under-represented. Here, we report the example of a semi-synthetic natural product derivative-ISIR-005-that stabilizes the cancer-relevant interaction of the adaptor protein 14-3-3 and Gab2. The crystal structure of ISIR-005 in complex with 14-3-3 and the binding motif of Gab2 comprising two phosphorylation sites (Gab2pS210pT391) showed how the stabilizing molecule binds to the rim-of-the-interface of the protein complex. Only in the direct vicinity of 14-3-3/Gab2pT391 site is a pre-formed pocket occupied by ISIR-005; binding of the Gab2pS210 motif to 14-3-3 does not create an interface pocket suitable for the molecule. Accordingly, ISIR-005 only stabilizes the binding of the Gab2pT391 but not the Gab2pS210 site. This study represents structural and biochemical proof of the druggability of the 14-3-3/Gab2 PPI interface with important implications for the development of PPI stabilizers.

Small-Molecule Stabilization of the 14-3-3/Gab2 Protein-Protein Interaction (PPI) Interface.,Bier D, Bartel M, Sies K, Halbach S, Higuchi Y, Haranosono Y, Brummer T, Kato N, Ottmann C ChemMedChem. 2016 Apr 19;11(8):911-8. doi: 10.1002/cmdc.201500484. Epub 2015 Dec , 8. PMID:26644359^[6]

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

References

↑ Dubois T, Rommel C, Howell S, Steinhussen U, Soneji Y, Morrice N, Moelling K, Aitken A. 14-3-3 is phosphorylated by casein kinase I on residue 233. Phosphorylation at this site in vivo regulates Raf/14-3-3 interaction. J Biol Chem. 1997 Nov 14;272(46):28882-8. PMID:9360956
↑ Zheng W, Zhang Z, Ganguly S, Weller JL, Klein DC, Cole PA. Cellular stabilization of the melatonin rhythm enzyme induced by nonhydrolyzable phosphonate incorporation. Nat Struct Biol. 2003 Dec;10(12):1054-7. Epub 2003 Oct 26. PMID:14578935 doi:10.1038/nsb1005
↑ Tsuruta F, Sunayama J, Mori Y, Hattori S, Shimizu S, Tsujimoto Y, Yoshioka K, Masuyama N, Gotoh Y. JNK promotes Bax translocation to mitochondria through phosphorylation of 14-3-3 proteins. EMBO J. 2004 Apr 21;23(8):1889-99. Epub 2004 Apr 8. PMID:15071501 doi:10.1038/sj.emboj.7600194
↑ Ganguly S, Weller JL, Ho A, Chemineau P, Malpaux B, Klein DC. Melatonin synthesis: 14-3-3-dependent activation and inhibition of arylalkylamine N-acetyltransferase mediated by phosphoserine-205. Proc Natl Acad Sci U S A. 2005 Jan 25;102(4):1222-7. Epub 2005 Jan 11. PMID:15644438 doi:0406871102
↑ Gu YM, Jin YH, Choi JK, Baek KH, Yeo CY, Lee KY. Protein kinase A phosphorylates and regulates dimerization of 14-3-3 epsilon. FEBS Lett. 2006 Jan 9;580(1):305-10. Epub 2005 Dec 19. PMID:16376338 doi:S0014-5793(05)01485-7
↑ Bier D, Bartel M, Sies K, Halbach S, Higuchi Y, Haranosono Y, Brummer T, Kato N, Ottmann C. Small-Molecule Stabilization of the 14-3-3/Gab2 Protein-Protein Interaction (PPI) Interface. ChemMedChem. 2016 Apr 19;11(8):911-8. doi: 10.1002/cmdc.201500484. Epub 2015 Dec , 8. PMID:26644359 doi:http://dx.doi.org/10.1002/cmdc.201500484