Atomic Analysis of Protein-Protein Interfaces with Known Inhibitors: The 2P2I Database

PLoS One

Marie-Jeanne Basse¹  Xavier Morelli¹  Philippe Roche¹  Raphaël Bourgeas¹ 

[1] Laboratoire Interactions et Modulateurs de Réponses (UPR3243), Centre National de la Recherche Scientifique (CNRS) & Aix-Marseille Universités, Institut de Microbiologie de la Méditerranée (IMM), Marseille, France

关键词: Hydrogen bonding;    Principal component analysis;    Protein structure databases;    Small molecules;    Proteomic databases;    Protein structure;    Database searching;    Protein-protein interactions;   

DOI  :  10.1371/journal.pone.0009598

学科分类：医学（综合）

来源: Public Library of Science

【 摘 要 】

Background In the last decade, the inhibition of protein-protein interactions (PPIs) has emerged from both academic and private research as a new way to modulate the activity of proteins. Inhibitors of these original interactions are certainly the next generation of highly innovative drugs that will reach the market in the next decade. However, in silico design of such compounds still remains challenging.Methodology/Principal Findings Here we describe this particular PPI chemical space through the presentation of 2P2IDB, a hand-curated database dedicated to the structure of PPIs with known inhibitors. We have analyzed protein/protein and protein/inhibitor interfaces in terms of geometrical parameters, atom and residue properties, buried accessible surface area and other biophysical parameters. The interfaces found in 2P2IDB were then compared to those of representative datasets of heterodimeric complexes. We propose a new classification of PPIs with known inhibitors into two classes depending on the number of segments present at the interface and corresponding to either a single secondary structure element or to a more globular interacting domain. 2P2IDB complexes share global shape properties with standard transient heterodimer complexes, but their accessible surface areas are significantly smaller. No major conformational changes are seen between the different states of the proteins. The interfaces are more hydrophobic than general PPI's interfaces, with less charged residues and more non-polar atoms. Finally, fifty percent of the complexes in the 2P2IDB dataset possess more hydrogen bonds than typical protein-protein complexes. Potential areas of study for the future are proposed, which include a new classification system consisting of specific families and the identification of PPI targets with high druggability potential based on key descriptors of the interaction.Conclusions 2P2I database stores structural information about PPIs with known inhibitors and provides a useful tool for biologists to assess the potential druggability of their interfaces. The database can be accessed at http://2p2idb.cnrs-mrs.fr.

【 授权许可】

CC BY