Dataset Information

Conformational Changes in the Cytoplasmic Region of KIR3DL1 upon Interaction with SHP-2.

ABSTRACT: KIR3DL1 is an inhibitory killer cell immunoglobulin-like receptor (KIR) that negatively regulates natural killer cell cytotoxicity. The KIR3DL1 cytoplasmic region (3DL1-cyto) is disordered and can be dissected into three segments: (I) H340-V351; (II) M352-D371; and (III) P372-P423. NMR studies indicate that segment II can dynamically adopt a loop-like conformation, and segments I and III can form dynamic helices that may mediate binding to membranes, particularly in the region around the N-terminal (N) immunoreceptor tyrosine-based inhibitory motif (ITIM), consistent with its role in signaling. Furthermore, individual SH2 domains of SHP-2 strongly engage with the unphosphorylated N-ITIM of 3DL1-cyto, while binding of the tandem SHP-2 SH2 domains to the bis-phosphorylated ITIMs results in more extensive conformational changes in segments I and III. The findings enhance our understanding of KIR function and how ITIMs in a target receptor operate in concert to engage the tandem SH2 domains of SHP-2.

SUBMITTER: Cheng H

PROVIDER: S-EPMC6447435 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Conformational Changes in the Cytoplasmic Region of KIR3DL1 upon Interaction with SHP-2.

Cheng Hong H Schwell Vered V Curtis Brett R BR Fazlieva Ruzaliya R Roder Heinrich H Campbell Kerry S KS

Structure (London, England : 1993) 20190214 4

KIR3DL1 is an inhibitory killer cell immunoglobulin-like receptor (KIR) that negatively regulates natural killer cell cytotoxicity. The KIR3DL1 cytoplasmic region (3DL1-cyto) is disordered and can be dissected into three segments: (I) H340-V351; (II) M352-D371; and (III) P372-P423. NMR studies indicate that segment II can dynamically adopt a loop-like conformation, and segments I and III can form dynamic helices that may mediate binding to membranes, particularly in the region around the N-termi ...[more]

PMID: 30773397

Similar Datasets

Project description:Protein-protein interactions represent difficult but increasingly important targets for the design of therapeutic compounds able to interfere with biological processes. Recently, fragment-based strategies have been proposed as attractive approaches for the elaboration of protein-protein surface inhibitors from fragment-like molecules. One major challenge in targeting protein-protein interactions is related to the structural adaptation of the protein surface upon molecular recognition. Methods capable of identifying subtle conformational changes of proteins upon fragment binding are therefore required at the early steps of the drug design process. In this report we present a fast NMR method able to probe subtle conformational changes upon fragment binding. The approach relies on the comparison of experimental fragment-induced Chemical Shift Perturbation (CSP) of amine protons to CSP simulated for a set of docked fragment poses, considering the ring-current effect from fragment binding. We illustrate the method by the retrospective analysis of the complex between the anti-apoptotic Bcl-xL protein and the fragment 4'-fluoro-[1,1'-biphenyl]-4-carboxylic acid that was previously shown to bind one of the Bcl-xL hot spots. The CSP-based approach shows that the protein undergoes a subtle conformational rearrangement upon interaction, for residues located in helices [Formula: see text]2, [Formula: see text]3 and the very beginning of [Formula: see text]5. Our observations are corroborated by residual dipolar coupling measurements performed on the free and fragment-bound forms of the Bcl-xL protein. These NMR-based results are in total agreement with previous molecular dynamic calculations that evidenced a high flexibility of Bcl-xL around the binding site. Here we show that CSP of protein amine protons are useful and reliable structural probes. Therefore, we propose to use CSP simulation to assess protein conformational changes upon ligand binding in the fragment-based drug design approach.

Dataset Information

Conformational Changes in the Cytoplasmic Region of KIR3DL1 upon Interaction with SHP-2.

Publications

Conformational Changes in the Cytoplasmic Region of KIR3DL1 upon Interaction with SHP-2.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets