PDBsum entry 6hep

Signaling protein

PDB id: 6hep

Contents

Protein chains

230 a.a.

15 a.a.

Ligands

ETE ×2

Waters ×735

PDB id:

6hep

Name:

Signaling protein

Title:

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

Structure:

14-3-3 protein beta/alpha. Chain: a, b, c, d. Synonym: protein 1054,protein kinasE C inhibitor protein 1,kcip-1. Engineered: yes. Cystic fibrosis transmembrane conductance regulator. Chain: e, f. Synonym: cftr,atp-binding cassette sub-family c member 7,channel conductance-controlling atpase,camp-dependent chloride channel. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: ywhab. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008. Synthetic: yes. Organism_taxid: 9606

Resolution:

1.86Å R-factor: 0.204 R-free: 0.251

Authors:

L.M.Stevers,C.Ottmann,L.Brunsveld

Key ref:

L.M.Stevers et al. (2018). A Thermodynamic Model for Multivalency in 14-3-3 Protein-Protein Interactions. J Am Chem Soc, 140, 14498-14510. PubMed id: 30296824 DOI: 10.1021/jacs.8b09618

Date:

20-Aug-18 Release date: 24-Oct-18

Protein chains

P31946  (1433B_HUMAN) -  14-3-3 protein beta/alpha from Homo sapiens

Seq: 246 a.a.

Struc: 230 a.a.

Protein chains

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

Seq: 1480 a.a.

Struc: 15 a.a.*

* PDB and UniProt seqs differ at 4 residue positions (black crosses)

Enzyme reactions

• Enzyme class: Chains E, F: 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: 10.1021/jacs.8b09618

J Am Chem Soc 140:14498-14510 (2018)

PubMed id: 30296824

A Thermodynamic Model for Multivalency in 14-3-3 Protein-Protein Interactions.

L.M.Stevers, P.J.de Vink, C.Ottmann, J.Huskens, L.Brunsveld.

ABSTRACT

Protein-protein interactions (PPIs) are at the core of molecular control over cellular function. Multivalency in PPI formation, such as via proteins with multiple binding sites and different valencies, requires fundamental understanding to address correlated challenges in pathologies and drug development. Thermodynamic binding models are needed to provide frameworks for describing multivalent PPIs. We established a model based on ditopic host-guest systems featuring the effective molarity, a hallmark property of multivalency, as a prime parameter governing the intramolecular binding in divalent interactions. By way of illustration, we study the interaction of the bivalent 14-3-3 protein scaffold with both the nonavalent CFTR and the hexavalent LRRK2 proteins, determining the underlying thermodynamics and providing insights into the role of individual sites in the context of the multivalent platform. Fitting of binding data reveals enthalpy-entropy correlation in both systems. Simulations of speciations for the entire phosphorylated protein domains reveal that the CFTR protein preferably binds to 14-3-3 by combinations including the strongest binding site pS768, but that other binding sites take over when this site is eliminated, leading to only a minor decrease in total affinity for 14-3-3. For LRRK2, two binding sites dominate the complex formation with 14-3-3, but the distantly located pS1444 site also plays a role in complex formation. Thermodynamic modeling of these multivalent PPIs allowed analyzing and predicting the effects of individual sites regarding their modulation via, for example, (de)phosphorylation or small-molecule targeting. The results specifically bring forward the potential of PPI stabilization, as an entry for drug discovery for multivalent PPIs.