Joosten RP

References (2)

Title : Facilities that make the PDB data collection more powerful - Lange_2020_Protein.Sci_29_330
Author(s) : Lange J , Baakman C , Pistorius A , Krieger E , Hooft R , Joosten RP , Vriend G
Ref : Protein Science , 29 :330 , 2020
Abstract : We describe a series of databases and tools that directly or indirectly support biomedical research on macromolecules, with focus on their applicability in protein structure bioinformatics research. DSSP, that determines secondary structures of proteins, has been updated to work well with extremely large structures in multiple formats. The PDBREPORT database that lists anomalies in protein structures has been remade to remove many small problems. These reports are now available as PDF-formatted files with a computer-readable summary. The VASE software has been added to analyze and visualize HSSP multiple sequence alignments for protein structures. The Lists collection of databases has been extended with a series of databases, most noticeably with a database that gives each protein structure a grade for usefulness in protein structure bioinformatics projects. The PDB-REDO collection of reanalyzed and re-refined protein structures that were solved by X-ray crystallography has been improved by dealing better with sugar residues and with hydrogen bonds, and adding many missing surface loops. All academic software underlying these protein structure bioinformatics applications and databases are now publicly accessible, either directly from the authors or from the GitHub software repository.
ESTHER : Lange_2020_Protein.Sci_29_330
PubMedSearch : Lange_2020_Protein.Sci_29_330
PubMedID: 31724231

Title : The Impact of Crystallization Conditions on Structure-Based Drug Design: A Case Study on the Methylene Blue\/Acetylcholinesterase Complex - Dym_2016_Protein.Sci_25_1096
Author(s) : Dym O , Song W , Felder CE , Roth E , Shnyrov V , Ashani Y , Xu Y , Joosten RP , Weiner L , Sussman JL , Silman I
Ref : Protein Science , 25 :1096 , 2016
Abstract : Structure-based drug design utilizes apo-protein or complex structures retrieved from the PDB. >57% of crystallographic PDB entries were obtained with polyethyleneglycols (PEGs) as precipitant and/or as cryoprotectant, but >6% of these report presence of individual ethyleneglycol oligomers. We report a case in which ethyleneglycol oligomers' presence in a crystal structure markedly affected the bound ligand's position. Specifically, we compared the positions of methylene blue and decamethonium in acetylcholinesterase complexes obtained using isomorphous crystals precipitated with PEG200 or ammonium sulfate. The ligands' positions within the active-site gorge in complexes obtained using PEG200 are influenced by presence of ethyleneglycol oligomers in both cases bound to W84 at the gorge's bottom, preventing interaction of the ligand's proximal quaternary group with its indole. Consequently, both ligands are approximately 3.0A further up the gorge than in complexes obtained using crystals precipitated with ammonium sulfate, in which the quaternary groups make direct pi-cation interactions with the indole. These findings have implications for structure-based drug design, since data for ligand-protein complexes with polyethyleneglycol as precipitant may not reflect the ligand's position in its absence, and could result in selecting incorrect drug discovery leads. Docking methylene blue into the structure obtained with PEG200, but omitting the ethyleneglycols, yields results agreeing poorly with the crystal structure; excellent agreement is obtained if they are included. Many proteins display features in which precipitants might lodge. It will be important to investigate presence of precipitants in published crystal structures, and whether it has resulted in misinterpreting electron density maps, adversely affecting drug design. This article is protected by copyright. All rights reserved.
ESTHER : Dym_2016_Protein.Sci_25_1096
PubMedSearch : Dym_2016_Protein.Sci_25_1096
PubMedID: 26990888
Gene_locus related to this paper: torca-ACHE