ArticlePLoS computational biology2016
Predicting Allosteric Effects from Orthosteric Binding in Hsp90-Ligand Interactions: Implications for Fragment-Based Drug Design.
Article in PLoS computational biology, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed, 29 citations in OpenAlex.
- Pushing the limits of hydrogen/deuterium exchange mass spectrometry to study protein:fragment low affinity interactions.Communications chemistry · 2025Article
- A hydrogen-deuterium exchange mass spectrometry-based protocol for protein-small molecule interaction analysis.Biophysics reports · 2023Article
- Mapping allosteric pathway in NIa-Pro using computational approach.Quantitative biology (Beijing, China) · 2023Article
- Advances in Hydrogen/Deuterium Exchange Mass Spectrometry and the Pursuit of Challenging Biological Systems.Chemical reviews · 2022Review
- Hydrogen-Deuterium Exchange Mass Spectrometry: A Novel Structural Biology Approach to Structure, Dynamics and Interactions of Proteins and Their Complexes.Life (Basel, Switzerland) · 2020Review
- Perturbed structural dynamics underlie inhibition and altered efflux of the multidrug resistance pump AcrB.Nature communications · 2020Article
- Synergistic Allostery in Multiligand-Protein Interactions.Biophysical journal · 2020Article
- HDX-MS reveals orthosteric and allosteric changes in apolipoprotein-D structural dynamics upon binding of progesterone.Protein science : a publication of the Protein Society · 2019Article
- Reversing allosteric communication: From detecting allosteric sites to inducing and tuning targeted allosteric response.PLoS computational biology · 2018Article
- Supporting the Identification of Novel Fragment-Based Positive Allosteric Modulators Using a Supervised Molecular Dynamics Approach: A Retrospective Analysis Considering the Human A2A Adenosine Receptor as a Key Example.Molecules (Basel, Switzerland) · 2017Article
- Ligand-mediated changes in conformational dynamics of NpmA: implications for ribosomal interactions.Scientific reports · 2016Article
- Allostery: An Overview of Its History, Concepts, Methods, and Applications.PLoS computational biology · 2016Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
6 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
A key question in mapping dynamics of protein-ligand interactions is to distinguish changes at binding sites from those associated with long range conformational changes upon binding at distal sites. This assumes a greater challenge when considering the interactions of low affinity ligands (dissociation constants, KD, in the μM range or lower). Amide hydrogen deuterium Exchange mass spectrometry (HDXMS) is a robust method that can provide both structural insights and dynamics information on both high affinity and transient protein-ligand interactions. In this study, an application of HDXMS for probing the dynamics of low affinity ligands to proteins is described using the N-terminal ATPase domain of Hsp90. Comparison of Hsp90 dynamics between high affinity natural inhibitors (KD ~ nM) and fragment compounds reveal that HDXMS is highly sensitive in mapping the interactions of both high and low affinity ligands. HDXMS reports on changes that reflect both orthosteric effects and allosteric changes accompanying binding. Orthosteric sites can be identified by overlaying HDXMS onto structural information of protein-ligand complexes. Regions distal to orthosteric sites indicate long range conformational changes with implications for allostery. HDXMS, thus finds powerful utility as a high throughput method for compound library screening to identify binding sites and describe allostery with important implications for fragment-based ligand discovery (FBLD).
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.