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Platinum: a database of experimentally measured effects of mutations on structurally defined protein-ligand complexes
Douglas E V Pires1, Tom L Blundell2, David B Ascher3
1Department of Biochemistry, University of Cambridge, Cambridge CB2 1GA, UK dpires@dcc.ufmg.br.
Abstract:
Drug resistance is a major challenge for the treatment of many diseases and a significant concern throughout the drug development process. The ability to understand and predict the effects of mutations on protein-ligand affinities and their roles in the emergence of resistance would significantly aid treatment and drug design strategies. In order to study and understand the impacts of missense mutations on the interaction of ligands with the proteome, we have developed Platinum (http://structure.bioc.cam.ac.uk/platinum). This manually curated, literature-derived database, comprising over 1000 mutations, associates for the first time experimental information on changes in affinity with three-dimensional structures of protein-ligand complexes. To minimize differences arising from experimental techniques and to directly compare binding affinities, Platinum considers only changes measured by the same group and with the same amino-acid sequence used for structure determination, providing a direct link between protein structure, how a ligand binds and how mutations alter the affinity of the ligand of the protein. We believe Platinum will be an invaluable resource for understanding the effects of mutations that give rise to drug resistance, a major problem emerging in pandemics including those caused by the influenza virus, in infectious diseases such as tuberculosis, in cancer and in many other life-threatening illnesses.
Insights
Platinum is a new database linking protein structures, ligand binding, and mutation effects. It helps predict how mutations cause drug resistance, aiding treatment and drug design.
Area of Science:
- Biochemistry
- Structural Biology
- Drug Discovery
Background:
- Drug resistance is a major challenge in treating diseases and developing new therapeutics.
- Understanding how mutations affect protein-ligand interactions is crucial for effective treatment and drug design.
- Predicting the impact of genetic variations on drug efficacy is a significant unmet need.
Purpose of the Study:
- To develop a comprehensive resource for studying the impact of missense mutations on protein-ligand interactions.
- To create a link between experimental data on affinity changes and 3D structural information of protein-ligand complexes.
- To provide a tool for understanding the molecular basis of drug resistance.
Main Methods:
- Developed Platinum, a manually curated, literature-derived database.
- Included over 1000 mutations with associated experimental affinity changes.
- Focused on affinity changes measured by the same research group using the same experimental conditions and amino acid sequences to ensure comparability.
Main Results:
- Platinum integrates experimental affinity data with 3D structural information for protein-ligand complexes.
- The database provides direct links between protein structure, ligand binding mechanisms, and the effects of mutations.
- It offers a valuable resource for analyzing how mutations alter ligand binding affinity.
Conclusions:
- Platinum serves as an invaluable resource for understanding mutation-driven drug resistance.
- The database can aid in the development of novel therapeutic strategies and drug design.
- It has broad applications in infectious diseases, cancer, and other life-threatening illnesses.