ISDA: 11SI

Deposition Date 2026-03-11

Release Date 2026-08-26

Last Version Date 2026-09-30

Entry Detail

PDB ID:

11SI

Keywords:

PROTEIN BINDING

Title:

Covalent stabilizer compound 15A for the interaction between 14-3-3 sigma and Estrogen receptor-alpha peptide

Biological Source:

Source Organism(s):

Homo sapiens (Taxon ID: 9606)

Expression System(s):

Escherichia coli

Method Details:

Experimental Method:

X-RAY DIFFRACTION

Resolution:

2.50 Å

R-Value Free:

0.27

R-Value Work:

0.24

R-Value Observed:

0.24

Space Group:

C 2 2 21

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Macromolecular Entities

Structures with similar UniProt ID

Structural Superimposition Protein Blast

Polymer Type:polypeptide(L)
Molecule:14-3-3 protein sigma
Gene (Uniprot):SFN
Chain IDs:A, B (auth: C)
Chain Length:253
Number of Molecules:2
Biological Source:Homo sapiens

UniProt ID:P31947 Pfam ID:PF00244

Structures with similar UniProt ID

Structural Superimposition Protein Blast

Polymer Type:polypeptide(L)
Molecule:Estrogen receptor
Gene (Uniprot):ESR1
Chain IDs:C (auth: X), D (auth: Y)
Chain Length:15
Number of Molecules:2
Biological Source:Homo sapiens

UniProt ID:P03372 Pfam ID:PF12743

Modified Residue

Compound ID	Chain ID	Parent Comp ID	Details	2D Image
TPO	C, D	THR	modified residue

Ligand Molecules

A1DAJ

Primary Citation

Covalent Stabilizers of the Interaction Between 14-3-3 sigma and Estrogen Receptor‐ alpha.

Jain, R, Knapp, M, Kochanek, S.E, Lewis, A, McGregor, L.M, Stojkovic, V, Tang, J, Tsang, T, Yan, K, Yifru, A, Zhu, Q, Fabbiani, F, Feng, G, Frank, A.O, Fuller, J, Jahnke, W, Jansen, J.M, Jo, J, Li, M, Lipps, J, Lu, Y, Mladenovic, T, Piechon, P, Rogemoser, P, Wang, F, Yang, S, Skepper, C.K.Show

Acs Med.Chem.Lett. 17 2006 2016 (2026)

PMID: 42741630 DOI: 10.1021/acsmedchemlett.6c00325

Abstact

Selective stabilization of complexes formed by the hub protein 14-3-3 represents an emerging mechanism for the modulation of therapeutically relevant targets. In this letter, we describe a hit-finding campaign designed to identify small molecule stabilizers of the interaction between 14-3-3sigma and the estrogen receptor alpha (ERalpha). Four structurally distinct hits were identified and validated using a combination of biochemical assays and biophysical techniques. Ternary complex crystal structures revealed that all four hit compounds form a covalent bond with Cys38 of 14-3-3sigma via four different electrophilic warheads. Structure-based optimization of the most promising hit compound 9 led to dramatic improvements in stabilization activity and selectivity that exceeded the complex natural product fusicoccin A.

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Primary Citation of related structures

Abstact

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