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Journal of Computational Chemistry Dec 2009We describe the testing and release of AutoDock4 and the accompanying graphical user interface AutoDockTools. AutoDock4 incorporates limited flexibility in the receptor....
We describe the testing and release of AutoDock4 and the accompanying graphical user interface AutoDockTools. AutoDock4 incorporates limited flexibility in the receptor. Several tests are reported here, including a redocking experiment with 188 diverse ligand-protein complexes and a cross-docking experiment using flexible sidechains in 87 HIV protease complexes. We also report its utility in analysis of covalently bound ligands, using both a grid-based docking method and a modification of the flexible sidechain technique.
Topics: Ligands; Models, Molecular; Protein Binding; Proteins; Software
PubMed: 19399780
DOI: 10.1002/jcc.21256 -
Bioinformatics (Oxford, England) Feb 2020The use of experimental information has been demonstrated to increase the success rate of computational macromolecular docking. Many methods use information to...
MOTIVATION
The use of experimental information has been demonstrated to increase the success rate of computational macromolecular docking. Many methods use information to post-filter the simulation output while others drive the simulation based on experimental restraints, which can become problematic for more complex scenarios such as multiple binding interfaces.
RESULTS
We present a novel method for including interface information into protein docking simulations within the LightDock framework. Prior to the simulation, irrelevant regions from the receptor are excluded for sampling (filter of initial swarms) and initial ligand poses are pre-oriented based on ligand input information. We demonstrate the applicability of this approach on the new 55 cases of the Protein-Protein Docking Benchmark 5, using different amounts of information. Even with incomplete or incorrect information, a significant improvement in performance is obtained compared to blind ab initio docking.
AVAILABILITY AND IMPLEMENTATION
The software is supported and freely available from https://github.com/brianjimenez/lightdock and analysis data from https://github.com/brianjimenez/lightdock_bm5.
SUPPLEMENTARY INFORMATION
Supplementary data are available at Bioinformatics online.
Topics: Computational Biology; Ligands; Proteins; Software
PubMed: 31418773
DOI: 10.1093/bioinformatics/btz642 -
Molecules (Basel, Switzerland) Jan 2021Reactions of cyclometalated compounds are numerous. This account is focused on one of such reactions, the exchange of cyclometalated ligands, a reaction between a... (Review)
Review
Reactions of cyclometalated compounds are numerous. This account is focused on one of such reactions, the exchange of cyclometalated ligands, a reaction between a cyclometalated compound and an incoming ligand that replaces a previously cyclometalated ligand to form a new metalacycle: + H-C*~Z ⇄ + H-C~Y. Originally discovered for Pd complexes with Y/Z = N, P, S, the exchange appeared to be a mechanistically challenging, simple, and convenient routine for the synthesis of cyclopalladated complexes. Over four decades it was expanded to cyclometalated derivatives of platinum, ruthenium, manganese, rhodium, and iridium. The exchange, which is also questionably referred to as transcyclometalation, offers attractive synthetic possibilities and assists in disclosing key mechanistic pathways associated with the C-H bond activation by transition metal complexes and C-M bond cleavage. Both synthetic and mechanistic aspects of the exchange are reviewed and discussed.
Topics: Ligands; Metals; Molecular Structure; Organometallic Compounds
PubMed: 33401624
DOI: 10.3390/molecules26010210 -
Nature Communications Sep 2023Many orphan G protein-coupled receptors (GPCRs) remain understudied because their endogenous ligands are unknown. Here, we show that a group of class A/rhodopsin-like...
Many orphan G protein-coupled receptors (GPCRs) remain understudied because their endogenous ligands are unknown. Here, we show that a group of class A/rhodopsin-like orphan GPCRs including GPR61, GPR161 and GPR174 increase the cAMP level similarly to fully activated D1 dopamine receptor (D1R). We report cryo-electron microscopy structures of the GPR61‒G, GPR161‒G and GPR174‒G complexes without any exogenous ligands. The GPR174 structure reveals that endogenous lysophosphatidylserine (lysoPS) is copurified. While GPR174 fails to respond to exogenous lysoPS, likely owing to its maximal activation by the endogenous ligand, GPR174 mutants with lower ligand binding affinities can be specifically activated by lysoPS but not other lipids, in a dose-dependent manner. Moreover, GPR174 adopts a non-canonical G coupling mode. The structures of GPR161 and GPR61 reveal that the second extracellular loop (ECL2) penetrates into the orthosteric pocket, possibly contributing to constitutive activity. Our work definitively confirms lysoPS as an endogenous GPR174 ligand and suggests that high constitutive activity of some orphan GPCRs could be accounted for by their having naturally abundant ligands.
Topics: Ligands; Cryoelectron Microscopy; Signal Transduction; Receptors, Dopamine D1
PubMed: 37737235
DOI: 10.1038/s41467-023-41654-3 -
Nature Communications Jul 2023Indirect cell-cell interactions mediated by secreted proteins and their plasma membrane receptors play essential roles for regulating intercellular signaling. However,...
Indirect cell-cell interactions mediated by secreted proteins and their plasma membrane receptors play essential roles for regulating intercellular signaling. However, systematic profiling of the interactions between living cell surface receptors and secretome from neighboring cells remains challenging. Here we develop a chemical proteomics approach, termed interaction-guided crosslinking (IGC), to identify ligand-receptor interactions in situ. By introducing glycan-based ligation and click chemistry, the IGC approach via glycan-to-glycan crosslinking successfully captures receptors from as few as 0.1 million living cells using only 10 ng of secreted ligand. The unparalleled sensitivity and selectivity allow systematic crosslinking and identification of ligand-receptor complexes formed between cell secretome and surfaceome in an unbiased and all-to-all manner, leading to the discovery of a ligand-receptor interaction between pancreatic cancer cell-secreted urokinase (PLAU) and neuropilin 1 (NRP1) on pancreatic cancer-associated fibroblasts. This approach is thus useful for systematic exploring new ligand-receptor pairs and discovering critical intercellular signaling events.
Topics: Ligands; Proteomics; Signal Transduction; Cell Communication; Biological Transport
PubMed: 37438365
DOI: 10.1038/s41467-023-39881-9 -
Current Opinion in Structural Biology Feb 2022In standard crystallographic refinement of biomacromolecules, the crystallographic raw data are supplemented by empirical restraints that ensure that the structure makes... (Review)
Review
In standard crystallographic refinement of biomacromolecules, the crystallographic raw data are supplemented by empirical restraints that ensure that the structure makes chemical sense. These restraints are typically accurate for amino acids and nucleic acids, but less so for cofactors, substrates, inhibitors, ligands and metal sites. In quantum refinement, this potential is replaced by more accurate quantum mechanical (QM) calculations. Several implementations have been presented, differing in the level of QM and whether it is used for the entire structure or only for a site of particular interest. It has been shown that the method can improve and correct errors in crystal structures and that it can be used to determine protonation and tautomeric states of various ligands and to decide what is really seen in the structure by refining different interpretations and using standard crystallographic and QM quality measures to decide which fits the structure best.
Topics: Crystallography, X-Ray; Ligands; Models, Molecular; Quantum Theory
PubMed: 34392061
DOI: 10.1016/j.sbi.2021.07.002 -
Methods in Cell Biology 2021We compare the GPCR-ligand interactions and highlight important residues for recognition in purinergic receptors-from both X-ray crystallographic and cryo-EM structures.... (Review)
Review
We compare the GPCR-ligand interactions and highlight important residues for recognition in purinergic receptors-from both X-ray crystallographic and cryo-EM structures. These include A and A adenosine receptors, and P2Y and P2Y receptors that respond to ADP and other nucleotides. These receptors are important drug discovery targets for immune, metabolic and nervous system disorders. In most cases, orthosteric ligands are represented, except for one allosteric P2Y antagonist. This review catalogs the residues and regions that engage in contacts with ligands or with other GPCR protomers in dimeric forms. Residues that are in proximity to bound ligands within purinergic GPCR families are correlated. There is extensive conservation of recognition motifs between adenosine receptors, but the P2Y and P2Y receptors are each structurally distinct in their ligand recognition. Identifying common interaction features for ligand recognition within a receptor class that has multiple structures available can aid in the drug discovery process.
Topics: Dimerization; Drug Discovery; Humans; Ligands
PubMed: 34752329
DOI: 10.1016/bs.mcb.2021.06.001 -
ACS Nano Feb 2023Herein, we present a generalizable and versatile strategy to engineer synthetic DNA ligand-binding devices that can be programmed to load and release a specific ligand...
Herein, we present a generalizable and versatile strategy to engineer synthetic DNA ligand-binding devices that can be programmed to load and release a specific ligand at a defined temperature. We do so by re-engineering two model DNA-based receptors: a triplex-forming bivalent DNA-based receptor that recognizes a specific DNA sequence and an ATP-binding aptamer. The temperature at which these receptors load/release their ligands can be finely modulated by controlling the entropy associated with the linker connecting the two ligand-binding domains. The availability of a set of receptors with tunable and reversible temperature dependence allows achieving complex load/release behavior such as sustained ligand release over a wide temperature range. Similar programmable thermo-responsive synthetic ligand-binding devices can be of utility in applications such as drug delivery and production of smart materials.
Topics: Ligands; Receptors, Artificial; DNA; Drug Delivery Systems; Entropy
PubMed: 36689298
DOI: 10.1021/acsnano.2c07039 -
Viruses Mar 2022Surface plasmon resonance and biolayer interferometry are two common real-time and label-free assays that quantify binding events by providing kinetic parameters. There... (Review)
Review
Surface plasmon resonance and biolayer interferometry are two common real-time and label-free assays that quantify binding events by providing kinetic parameters. There is increased interest in using these techniques to characterize whole virus-ligand interactions, as the methods allow for more accurate characterization than that of a viral subunit-ligand interaction. This review aims to summarize and evaluate the uses of these technologies specifically in virus-ligand and virus-like particle-ligand binding cases to guide the field towards studies that apply these robust methods for whole virus-based studies.
Topics: Biological Assay; Biosensing Techniques; Interferometry; Kinetics; Ligands; Surface Plasmon Resonance
PubMed: 35458446
DOI: 10.3390/v14040717 -
Annual Review of Cell and Developmental... Oct 2023Cell-cell communication is critical for the development and function of multicellular organisms. A crucial means by which cells communicate with one another is physical... (Review)
Review
Cell-cell communication is critical for the development and function of multicellular organisms. A crucial means by which cells communicate with one another is physical interactions between receptors on one cell and their ligands on a neighboring cell. ligand:receptor interactions activate the receptor, ultimately leading to changes in the fate of the receptor-expressing cells. Such signaling is known to be critical for the functions of cells in the nervous and immune systems, among others. Historically, interactions are the primary conceptual framework for understanding cell-cell communication. However, cells often coexpress many receptors and ligands, and a subset of these has been reported to interact in and profoundly impact cell functions. interactions likely constitute a fundamental, understudied regulatory mechanism in cell biology. Here, I discuss how interactions between membrane receptors and ligands regulate immune cell functions, and I also highlight outstanding questions in the field.
Topics: Ligands; Cell Communication; Signal Transduction
PubMed: 37339682
DOI: 10.1146/annurev-cellbio-120420-103941