Small Glycols Discover Cryptic Pockets on Proteins for Fragment-based Approaches

Bansia, Harsh; Mahanta, Pranjal; Yennawar, Neela H.; Ramakumar, Suryanarayanarao

doi:10.1101/605121

Cited by 1 publication

(1 citation statement)

References 74 publications

(86 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Moreover, ordered polyethylene glycol (PEG) molecules from several previous structures illustrate the potential for future ligand design efforts to “grow” from one of these initial fragment hits (5RFO) toward the mobile Glu290 and Cys128. This observation reinforces the idea that molecules from crystallization solutions, such as glycols, can reveal useful features like cryptic binding pockets 30 .…”

Section: Resultssupporting

confidence: 85%

The temperature-dependent conformational ensemble of SARS-CoV-2 main protease (M^pro)

Ebrahim

Riley

Kumaran

et al. 2021

Preprint

View full text Add to dashboard Cite

The COVID-19 pandemic, instigated by the SARS-CoV-2 coronavirus, continues to plague the globe. The SARS-CoV-2 main protease, or Mpro, is a promising target for development of novel antiviral therapeutics. Previous X-ray crystal structures of Mpro were obtained at cryogenic temperature or room temperature only. Here we report a series of high-resolution crystal structures of unliganded Mpro across multiple temperatures from cryogenic to physiological, and another at high humidity. We interrogate these datasets with parsimonious multiconformer models, multi-copy ensemble models, and isomorphous difference density maps. Our analysis reveals a temperature-dependent conformational landscape for Mpro, including a mobile water interleaved between the catalytic dyad, mercurial conformational heterogeneity in a key substrate-binding loop, and a far-reaching intramolecular network bridging the active site and dimer interface. Our results may inspire new strategies for antiviral drug development to counter-punch COVID-19.

show abstract

Section: Resultssupporting

confidence: 85%

The temperature-dependent conformational ensemble of SARS-CoV-2 main protease (M^pro)

Ebrahim

Riley

Kumaran

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

Small Glycols Discover Cryptic Pockets on Proteins for Fragment-based Approaches

Cited by 1 publication

References 74 publications

The temperature-dependent conformational ensemble of SARS-CoV-2 main protease (M^pro)

The temperature-dependent conformational ensemble of SARS-CoV-2 main protease (M^pro)

Contact Info

Product

Resources

About

Small Glycols Discover Cryptic Pockets on Proteins for Fragment-based Approaches

Cited by 1 publication

References 74 publications

The temperature-dependent conformational ensemble of SARS-CoV-2 main protease (Mpro)

The temperature-dependent conformational ensemble of SARS-CoV-2 main protease (Mpro)

Contact Info

Product

Resources

About

The temperature-dependent conformational ensemble of SARS-CoV-2 main protease (M^pro)

The temperature-dependent conformational ensemble of SARS-CoV-2 main protease (M^pro)