The chemical component dictionary: complete descriptions of constituent molecules in experimentally determined 3D macromolecules in the Protein Data Bank

Westbrook, John D.; Shao, Chenghua; Feng, Zhang; Zhuravleva, Marina A.; Velankar, Sameer; Young, Jasmine

doi:10.1093/bioinformatics/btu789

Cited by 134 publications

(126 citation statements)

References 17 publications

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“…The PDB CCD is the place of reference for obtaining codes, names and chemical descriptions of the very building blocks that structural biology relies upon: monomers. These are stored in files containing a topological description of the monomer along with example Cartesian coordinates, extracted from a deposited experimental structure, and/or computationally idealized coordinates (Westbrook et al, 2015). Both sets are available from the PDB CCD in SDF format (Molecular Design Ltd,), and can be inspected with either PyMOL (v,8; Schrö -dinger) or UCSF Chimera (Pettersen et al, 2004).…”

Section: Dictionaries For Sugarsmentioning

confidence: 99%

Strategies for carbohydrate model building, refinement and validation

Agirre

2017

Acta Crystallogr D Struct Biol

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Sugars are the most stereochemically intricate family of biomolecules and present substantial challenges to anyone trying to understand their nomenclature, reactions or branched structures. Current crystallographic programs provide an abstraction layer allowing inexpert structural biologists to build complete protein or nucleic acid model components automatically either from scratch or with little manual intervention. This is, however, still not generally true for sugars. The need for carbohydrate-specific building and validation tools has been highlighted a number of times in the past, concomitantly with the introduction of a new generation of experimental methods that have been ramping up the production of protein–sugar complexes and glycoproteins for the past decade. While some incipient advances have been made to address these demands, correctly modelling and refining carbohydrates remains a challenge. This article will address many of the typical difficulties that a structural biologist may face when dealing with carbohydrates, with an emphasis on problem solving in the resolution range where X-ray crystallography and cryo-electron microscopy are expected to overlap in the next decade.

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Section: Dictionaries For Sugarsmentioning

confidence: 99%

Strategies for carbohydrate model building, refinement and validation

Agirre

2017

Acta Crystallogr D Struct Biol

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“…For final thioether cyclization of c(MpSIpYVA), the N-terminus of the peptide was chloroacetylated using chloroacetic anhydride and N,N-diisopropylethylamine (DIEA), following established methods with minor modifications (38,48). For consistency in reporting structural information concerning macrocyclic peptides, the peptide-like unit containing the thioether bond is designated as the defined chemical component 48V (49,50). Cleavage of the peptides from the resin was achieved using a cocktail of Reagent K (TFA/Thioanisole/Water/Phenol/EDT:82.5:5:5:5:2 .5 v/v) and 1% Triisopropylsilane (TIPS) for 3 hours at room temperature.…”

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confidence: 99%

A trapped human PPM1A–phosphopeptide complex reveals structural features critical for regulation of PPM protein phosphatase activity

Debnath

Košek²,

Tagad

et al. 2018

Journal of Biological Chemistry

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Metal-dependent protein phosphatases (PPM) are evolutionarily unrelated to other serine/threonine protein phosphatases and are characterized by their requirement for supplementation with millimolar concentrations of Mg 2+ or Mn 2+ ions for activity in vitro. The crystal structure of human PPM1A (also known as PP2Cα), the first PPM structure determined, displays two tightly bound Mn 2+ ions in the active site and a small subdomain, termed the Flap, located adjacent to the active site. Some recent crystal structures of bacterial or plant PPM phosphatases have disclosed two tightly bound metal ions and an additional, third metal ion in the active site. Here, the crystal structure of the catalytic domain of human PPM1A, PPM1A cat , complexed with a cyclic phosphopeptide, c(MpSIpYVA), a cyclized variant of the activation loop of p38 MAPK (a physiological substrate of PPM1A), revealed three metal ions in the active site. The PPM1A cat D146E-c(MpSIpYVA) complex confirmed the presence of the anticipated third metal ion in the active site of metazoan PPM phosphatases. Biophysical and computational methods suggested that complex formation results in a slightly more compact solution conformation through reduced conformational flexibility of the Flap subdomain. We also observed that the position of the substrate in the active site allows solvent access to the labile third metal-binding site. Enzyme kinetics of PPM1A cat toward a phosphopeptide substrate supported a randomorder, bi-substrate mechanism, with substantial interaction between the bound substrate and the labile metal ion. This work illuminates the structural and thermodynamic basis of an innate mechanism regulating the activity of PPM phosphatases.Reversible protein phosphorylation signaling pathways are shaped by opposing actions of protein kinases and phosphatases. These pathways regulate the response of cells and organisms to changing environmental and physiological circumstances; dysregulation of these pathways underlies many human diseases. Although phosphorylated protein residues are dominated by phosphoserine (pSer) Trapped PPM1A-phosphopeptide complex 2 of phosphatases involved in reversing the pSer/pThr and pTyr modifications are more evenly divided (1-3). Analysis of global dynamics of pSer/pThr and pTyr-based signaling suggests distinct patterns of regulation (4). The phosphoprotein phosphatases (PPP), with 13 members, and the metal-dependent phosphatases (PPM), with 18 members, provide most of the serine/threonine protein phosphatase activity in human cells (5,6).The activity, substrate specificity, and subcellular localization of PPP phosphatases are regulated primarily by binding of regulatory or inhibitor subunits, of which over 100 have been identified in human cells (7,8). PPM phosphatases generally are monomeric, but regulation of their activity remains incompletely understood (9-11). The evolutionarily distinct PPP and PPM phosphatases both feature tightly-bound bi-metal clusters in their active sites, but only the PPM phosphatases req...

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“…Hence, the more detailed features of the GUI only relate to the editing of dictionary files. However, REEL will also read any of the chemical input formats, including the residues in the Chemical Components Dictionary (Westbrook et al, 2015), via their three-letter code.…”

Section: Overview Of Windows and Layoutmentioning

confidence: 99%

An editor for the generation and customization of geometry restraints

Moriarty

Draizen

Adams

2017

Acta Crystallogr D Struct Biol

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Chemical restraints for use in macromolecular structure refinement are produced by a variety of methods, including a number of programs that use chemical information to generate the required bond, angle, dihedral, chiral and planar restraints. These programs help to automate the process and therefore minimize the errors that could otherwise occur if it were performed manually. Furthermore, restraint-dictionary generation programs can incorporate chemical and other prior knowledge to provide reasonable choices of types and values. However, the use of restraints to define the geometry of a molecule is an approximation introduced with efficiency in mind. The representation of a bond as a parabolic function is a convenience and does not reflect the true variability in even the simplest of molecules. Another complicating factor is the interplay of the molecule with other parts of the macromolecular model. Finally, difficult situations arise from molecules with rare or unusual moieties that may not have their conformational space fully explored. These factors give rise to the need for an interactive editor for WYSIWYG interactions with the restraints and molecule. Restraints Editor, Especially Ligands (REEL) is a graphical user interface for simple and error-free editing along with additional features to provide greater control of the restraint dictionaries in macromolecular refinement.

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The chemical component dictionary: complete descriptions of constituent molecules in experimentally determined 3D macromolecules in the Protein Data Bank

Abstract: Supplementary data are available at Bioinformatics online.

Cited by 134 publications

References 17 publications

Strategies for carbohydrate model building, refinement and validation

Strategies for carbohydrate model building, refinement and validation

A trapped human PPM1A–phosphopeptide complex reveals structural features critical for regulation of PPM protein phosphatase activity

An editor for the generation and customization of geometry restraints

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