PDBsum entry 5d2d

Peptide binding protein

PDB id: 5d2d

Contents

Protein chains

229 a.a.

19 a.a.

Ligands

GLC-FRU ×2

Metals

_CL ×4

Waters ×196

PDB id:

5d2d

Name:

Peptide binding protein

Title:

Crystal structure of human 14-3-3 zeta in complex with cftr r-domain peptide ps753-ps768

Structure:

14-3-3 protein zeta/delta. Chain: a, b. Synonym: protein kinasE C inhibitor protein 1,kcip-1. Engineered: yes. Cystic fibrosis transmembrane conductance regulator. Chain: c. Fragment: unp residues 747-774. Synonym: cftr,atp-binding cassette sub-family c member 7,channel conductance-controlling atpase,camp-dependent chloride channel.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: ywhaz. Expressed in: escherichia coli. Expression_system_taxid: 562. Synthetic: yes. Organism_taxid: 9606

Resolution:

2.10Å R-factor: 0.195 R-free: 0.220

Authors:

L.M.Stevers,S.F.R.Leysen,C.Ottmann

Key ref:

L.M.Stevers et al. (2016). Characterization and small-molecule stabilization of the multisite tandem binding between 14-3-3 and the R domain of CFTR. Proc Natl Acad Sci U S A, 113, E1152. PubMed id: 26888287 DOI: 10.1073/pnas.1516631113

Date:

05-Aug-15 Release date: 16-Mar-16

Protein chains

P63104  (1433Z_HUMAN) -  14-3-3 protein zeta/delta from Homo sapiens

Seq: 245 a.a.

Struc: 229 a.a.

Protein chain

P13569  (CFTR_HUMAN) -  Cystic fibrosis transmembrane conductance regulator from Homo sapiens

Seq: 1480 a.a.

Struc: 19 a.a.

Enzyme reactions

• Enzyme class: Chain C: E.C.5.6.1.6 - channel-conductance-controlling ATPase.
• Reaction: ATP + H2O + closed Cl^- channel = ADP + phosphate + open Cl^- channel

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

DOI no: 10.1073/pnas.1516631113

Proc Natl Acad Sci U S A 113:E1152 (2016)

PubMed id: 26888287

Characterization and small-molecule stabilization of the multisite tandem binding between 14-3-3 and the R domain of CFTR.

L.M.Stevers, C.V.Lam, S.F.Leysen, F.A.Meijer, D.S.van Scheppingen, R.M.de Vries, G.W.Carlile, L.G.Milroy, D.Y.Thomas, L.Brunsveld, C.Ottmann.

ABSTRACT

Cystic fibrosis is a fatal genetic disease, most frequently caused by the retention of the CFTR (cystic fibrosis transmembrane conductance regulator) mutant protein in the endoplasmic reticulum (ER). The binding of the 14-3-3 protein to the CFTR regulatory (R) domain has been found to enhance CFTR trafficking to the plasma membrane. To define the mechanism of action of this protein-protein interaction, we have examined the interaction in vitro. The disordered multiphosphorylated R domain contains nine different 14-3-3 binding motifs. Furthermore, the 14-3-3 protein forms a dimer containing two amphipathic grooves that can potentially bind these phosphorylated motifs. This results in a number of possible binding mechanisms between these two proteins. Using multiple biochemical assays and crystal structures, we show that the interaction between them is governed by two binding sites: The key binding site of CFTR (pS768) occupies one groove of the 14-3-3 dimer, and a weaker, secondary binding site occupies the other binding groove. We show that fusicoccin-A, a natural-product tool compound used in studies of 14-3-3 biology, can stabilize the interaction between 14-3-3 and CFTR by selectively interacting with a secondary binding motif of CFTR (pS753). The stabilization of this interaction stimulates the trafficking of mutant CFTR to the plasma membrane. This definition of the druggability of the 14-3-3-CFTR interface might offer an approach for cystic fibrosis therapeutics.