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Comparative modeling and docking of chemokine-receptor interactions with Rosetta.
Wedemeyer MJ, Mueller BK, Bender BJ, Meiler J, Volkman BF
(2020) Biochem Biophys Res Commun 528: 389-397
MeSH Terms: Chemokines, Crystallography, X-Ray, Molecular Docking Simulation, Receptors, Chemokine, Software, Structural Homology, Protein
Show Abstract · Added March 21, 2020
Chemokine receptors are a subset of G protein-coupled receptors defined by the distinct property of binding small protein ligands in the chemokine family. Chemokine receptors recognize their ligands by a mechanism that is distinct from other class A GPCRs that bind peptides or small molecules. For this reason, structural information on other ligand-GPCR interactions are only indirectly relevant to understanding the chemokine receptor interface. Additionally, the experimentally determined structures of chemokine-GPCR complexes represent less than 3% of the known interactions of this complex, multi-ligand/multi-receptor network. To enable predictive modeling of the remaining 97% of interactions, a general in silico protocol was designed to utilize existing chemokine receptor crystal structures, co-crystal structures, and NMR ensembles of chemokines bound to receptor fragments. This protocol was benchmarked on the ability to predict each of the three published co-crystal structures, while being blinded to the target structure. Averaging ensembles selected from the top-ranking models reproduced up to 84% of the intermolecular contacts found in the crystal structure, with the lowest Cα-RMSD of the complex at 3.3 Å. The chemokine receptor N-terminus, unresolved in crystal structures, was included in the modeling and recapitulates contacts with known sulfotyrosine binding pockets seen in structures derived from experimental NMR data. This benchmarking experiment suggests that realistic homology models of chemokine-GPCR complexes can be generated by leveraging current structural data.
Copyright © 2019 Elsevier Inc. All rights reserved.
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6 MeSH Terms
Integrative Protein Modeling in RosettaNMR from Sparse Paramagnetic Restraints.
Kuenze G, Bonneau R, Leman JK, Meiler J
(2019) Structure 27: 1721-1734.e5
MeSH Terms: Animals, Humans, Molecular Docking Simulation, Molecular Dynamics Simulation, Nuclear Magnetic Resonance, Biomolecular, Protein Conformation, Software
Show Abstract · Added March 21, 2020
Computational methods to predict protein structure from nuclear magnetic resonance (NMR) restraints that only require assignment of backbone signals, hold great potential to study larger proteins. Ideally, computational methods designed to work with sparse data need to add atomic detail that is missing in the experimental restraints. We introduce a comprehensive framework into the Rosetta suite that uses NMR restraints derived from paramagnetic labeling. Specifically, RosettaNMR incorporates pseudocontact shifts, residual dipolar couplings, and paramagnetic relaxation enhancements. It continues to use backbone chemical shifts and nuclear Overhauser effect distance restraints. We assess RosettaNMR for protein structure prediction by folding 28 monomeric proteins and 8 homo-oligomeric proteins. Furthermore, the general applicability of RosettaNMR is demonstrated on two protein-protein and three protein-ligand docking examples. Paramagnetic restraints generated more accurate models for 85% of the benchmark proteins and, when combined with chemical shifts, sampled high-accuracy models (≤2Å) in 50% of the cases.
Copyright © 2019 Elsevier Ltd. All rights reserved.
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7 MeSH Terms
Upgraded molecular models of the human KCNQ1 potassium channel.
Kuenze G, Duran AM, Woods H, Brewer KR, McDonald EF, Vanoye CG, George AL, Sanders CR, Meiler J
(2019) PLoS One 14: e0220415
MeSH Terms: Humans, Hydrogen Bonding, KCNQ1 Potassium Channel, Lipids, Loss of Function Mutation, Models, Molecular, Molecular Docking Simulation, Molecular Dynamics Simulation, Protein Binding, Protein Conformation, Structure-Activity Relationship
Show Abstract · Added March 21, 2020
The voltage-gated potassium channel KCNQ1 (KV7.1) assembles with the KCNE1 accessory protein to generate the slow delayed rectifier current, IKS, which is critical for membrane repolarization as part of the cardiac action potential. Loss-of-function (LOF) mutations in KCNQ1 are the most common cause of congenital long QT syndrome (LQTS), type 1 LQTS, an inherited genetic predisposition to cardiac arrhythmia and sudden cardiac death. A detailed structural understanding of KCNQ1 is needed to elucidate the molecular basis for KCNQ1 LOF in disease and to enable structure-guided design of new anti-arrhythmic drugs. In this work, advanced structural models of human KCNQ1 in the resting/closed and activated/open states were developed by Rosetta homology modeling guided by newly available experimentally-based templates: X. leavis KCNQ1 and various resting voltage sensor structures. Using molecular dynamics (MD) simulations, the capacity of the models to describe experimentally established channel properties including state-dependent voltage sensor gating charge interactions and pore conformations, PIP2 binding sites, and voltage sensor-pore domain interactions were validated. Rosetta energy calculations were applied to assess the utility of each model in interpreting mutation-evoked KCNQ1 dysfunction by predicting the change in protein thermodynamic stability for 50 experimentally characterized KCNQ1 variants with mutations located in the voltage-sensing domain. Energetic destabilization was successfully predicted for folding-defective KCNQ1 LOF mutants whereas wild type-like mutants exhibited no significant energetic frustrations, which supports growing evidence that mutation-induced protein destabilization is an especially common cause of KCNQ1 dysfunction. The new KCNQ1 Rosetta models provide helpful tools in the study of the structural basis for KCNQ1 function and can be used to generate hypotheses to explain KCNQ1 dysfunction.
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Protection of abasic sites during DNA replication by a stable thiazolidine protein-DNA cross-link.
Thompson PS, Amidon KM, Mohni KN, Cortez D, Eichman BF
(2019) Nat Struct Mol Biol 26: 613-618
MeSH Terms: Crystallography, X-Ray, DNA Repair, DNA Replication, DNA, Single-Stranded, DNA-Binding Proteins, Escherichia coli, Escherichia coli Proteins, Humans, Molecular Docking Simulation, Protein Conformation, Thiazolidines
Show Abstract · Added August 26, 2019
Abasic (AP) sites are one of the most common DNA lesions that block replicative polymerases. 5-hydroxymethylcytosine binding, embryonic stem cell-specific protein (HMCES) recognizes and processes these lesions in the context of single-stranded DNA (ssDNA). A HMCES DNA-protein cross-link (DPC) intermediate is thought to shield the AP site from endonucleases and error-prone polymerases. The highly evolutionarily conserved SOS-response associated peptidase (SRAP) domain of HMCES and its Escherichia coli ortholog YedK mediate lesion recognition. Here we uncover the basis of AP site protection by SRAP domains from a crystal structure of the YedK DPC. YedK forms a stable thiazolidine linkage between a ring-opened AP site and the α-amino and sulfhydryl substituents of its amino-terminal cysteine residue. The thiazolidine linkage explains the remarkable stability of the HMCES DPC, its resistance to strand cleavage and the proteolysis requirement for resolution. Furthermore, its structure reveals that HMCES has specificity for AP sites in ssDNA at junctions found when replicative polymerases encounter the AP lesion.
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11 MeSH Terms
HLA-A*32:01 is strongly associated with vancomycin-induced drug reaction with eosinophilia and systemic symptoms.
Konvinse KC, Trubiano JA, Pavlos R, James I, Shaffer CM, Bejan CA, Schutte RJ, Ostrov DA, Pilkinton MA, Rosenbach M, Zwerner JP, Williams KB, Bourke J, Martinez P, Rwandamuriye F, Chopra A, Watson M, Redwood AJ, White KD, Mallal SA, Phillips EJ
(2019) J Allergy Clin Immunol 144: 183-192
MeSH Terms: Adolescent, Adult, Aged, Anti-Bacterial Agents, Drug Hypersensitivity Syndrome, Female, HLA-A Antigens, Humans, Male, Middle Aged, Molecular Docking Simulation, Vancomycin, Young Adult
Show Abstract · Added March 30, 2020
BACKGROUND - Vancomycin is a prevalent cause of the severe hypersensitivity syndrome drug reaction with eosinophilia and systemic symptoms (DRESS), which leads to significant morbidity and mortality and commonly occurs in the setting of combination antibiotic therapy, affecting future treatment choices. Variations in HLA class I in particular have been associated with serious T cell-mediated adverse drug reactions, which has led to preventive screening strategies for some drugs.
OBJECTIVE - We sought to determine whether variation in the HLA region is associated with vancomycin-induced DRESS.
METHODS - Probable vancomycin-induced DRESS cases were matched 1:2 with tolerant control subjects based on sex, race, and age by using BioVU, Vanderbilt's deidentified electronic health record database. Associations between DRESS and carriage of HLA class I and II alleles were assessed by means of conditional logistic regression. An extended sample set from BioVU was used to conduct a time-to-event analysis of those exposed to vancomycin with and without the identified HLA risk allele.
RESULTS - Twenty-three subjects met the inclusion criteria for vancomycin-associated DRESS. Nineteen (82.6%) of 23 cases carried HLA-A*32:01 compared with 0 (0%) of 46 of the matched vancomycin-tolerant control subjects (P = 1 × 10) and 6.3% of the BioVU population (n = 54,249, P = 2 × 10). Time-to-event analysis of DRESS development during vancomycin treatment among the HLA-A*32:01-positive group indicated that 19.2% had DRESS and did so within 4 weeks.
CONCLUSIONS - HLA-A*32:01 is strongly associated with vancomycin-induced DRESS in a population of predominantly European ancestry. HLA-A*32:01 testing could improve antibiotic safety, help implicate vancomycin as the causal drug, and preserve future treatment options with coadministered antibiotics.
Copyright © 2019 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
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13 MeSH Terms
Potent anti-influenza H7 human monoclonal antibody induces separation of hemagglutinin receptor-binding head domains.
Turner HL, Pallesen J, Lang S, Bangaru S, Urata S, Li S, Cottrell CA, Bowman CA, Crowe JE, Wilson IA, Ward AB
(2019) PLoS Biol 17: e3000139
MeSH Terms: Amino Acid Sequence, Animals, Antibodies, Neutralizing, Antibody Specificity, Baculoviridae, Binding Sites, Cloning, Molecular, Cryoelectron Microscopy, Gene Expression, Hemagglutinin Glycoproteins, Influenza Virus, Hydrogen Bonding, Immunoglobulin Fab Fragments, Influenza A virus, Molecular Docking Simulation, Protein Binding, Protein Conformation, alpha-Helical, Protein Conformation, beta-Strand, Protein Interaction Domains and Motifs, Recombinant Proteins, Sequence Alignment, Sequence Homology, Amino Acid, Sf9 Cells, Spodoptera
Show Abstract · Added March 31, 2019
Seasonal influenza virus infections can cause significant morbidity and mortality, but the threat from the emergence of a new pandemic influenza strain might have potentially even more devastating consequences. As such, there is intense interest in isolating and characterizing potent neutralizing antibodies that target the hemagglutinin (HA) viral surface glycoprotein. Here, we use cryo-electron microscopy (cryoEM) to decipher the mechanism of action of a potent HA head-directed monoclonal antibody (mAb) bound to an influenza H7 HA. The epitope of the antibody is not solvent accessible in the compact, prefusion conformation that typifies all HA structures to date. Instead, the antibody binds between HA head protomers to an epitope that must be partly or transiently exposed in the prefusion conformation. The "breathing" of the HA protomers is implied by the exposure of this epitope, which is consistent with metastability of class I fusion proteins. This structure likely therefore represents an early structural intermediate in the viral fusion process. Understanding the extent of transient exposure of conserved neutralizing epitopes also may lead to new opportunities to combat influenza that have not been appreciated previously.
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23 MeSH Terms
BCL::MolAlign: Three-Dimensional Small Molecule Alignment for Pharmacophore Mapping.
Brown BP, Mendenhall J, Meiler J
(2019) J Chem Inf Model 59: 689-701
MeSH Terms: Cheminformatics, Ligands, Molecular Docking Simulation, Monte Carlo Method, Protein Conformation, Small Molecule Libraries
Show Abstract · Added March 21, 2020
Small molecule flexible alignment is a critical component of both ligand- and structure-based methods in computer-aided drug discovery. Despite its importance, the availability of high-quality flexible alignment software packages is limited. Here, we present BCL::MolAlign, a freely available property-based molecular alignment program. BCL::MolAlign accommodates ligand flexibility through a combination of pregenerated conformers and on-the-fly bond rotation. BCL::MolAlign converges on alignment poses by sampling the relative orientations of mutually matching atom pairs between molecules through Monte Carlo Metropolis sampling. Across six diverse ligand data sets, BCL::MolAlign flexible alignment outperforms MOE, ROCS, and FLEXS in recovering native ligand binding poses. Moreover, the BCL::MolAlign alignment score is more predictive of ligand activity than maximum common substructure similarity across 10 data sets. Finally, on a recently published benchmark set of 20 high quality congeneric ligand-protein complexes, BCL::MolAlign is able to recover a larger fraction of native binding poses than maximum common substructure-based alignment and RosettaLigand. BCL::MolAlign can be obtained as part of the Biology and Chemistry Library (BCL) software package freely with an academic license or can be accessed via Web server at http://meilerlab.org/index.php/servers/molalign .
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Functional and structural similarity of human DNA primase [4Fe4S] cluster domain constructs.
Holt ME, Salay LE, O'Brien E, Barton JK, Chazin WJ
(2018) PLoS One 13: e0209345
MeSH Terms: Binding Sites, Circular Dichroism, Crystallography, X-Ray, DNA, DNA Primase, Molecular Docking Simulation, Nuclear Magnetic Resonance, Biomolecular, Oxidation-Reduction, Protein Binding, Protein Domains, Protein Structure, Secondary, RNA
Show Abstract · Added March 26, 2019
The regulatory subunit of human DNA primase has a C-terminal domain (p58C) that contains a [4Fe4S] cluster and binds DNA. Previous electrochemical analysis of a p58C construct revealed that its affinity for DNA is sensitive to the redox state of the [4Fe4S] cluster. Concerns about the validity of this conclusion have been raised, based in part on differences in X-ray crystal structures of the p58C272-464 construct used for that study and that of a N-terminally shifted p58C266-456 construct and consequently, an assumption that p58C272-464 has abnormal physical and functional properties. To address this controversy, a new p58C266-464 construct containing all residues was crystallized under the conditions previously used for crystallizing p58C272-464, and the solution structures of both constructs were assessed using circular dichroism and NMR spectroscopy. In the new crystal structure, p58C266-464 exhibits the same elements of secondary structure near the DNA binding site as observed in the crystal structure of p58C272-464. Moreover, in solution, circular dichroism and 15N,1H-heteronuclear single quantum coherence (HSQC) NMR spectra show there are no significant differences in the distribution of secondary structures or in the tertiary structure or the two constructs. To validate that the two constructs have the same functional properties, binding of a primed DNA template was measured using a fluorescence-based DNA binding assay, and the affinities for this substrate were the same (3.4 ± 0.5 μM and 2.7 ± 0.3 μM, respectively). The electrochemical properties of p58C266-464 were also measured and this p58C construct was able to engage in redox switching on DNA with the same efficiency as p58C272-464. Together, these results show that although p58C can be stabilized in different conformations in the crystalline state, in solution there is effectively no difference in the structure and functional properties of p58C constructs of different lengths.
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12 MeSH Terms
The role of HLA-A*33:01 in patients with cholestatic hepatitis attributed to terbinafine.
Fontana RJ, Cirulli ET, Gu J, Kleiner D, Ostrov D, Phillips E, Schutte R, Barnhart H, Chalasani N, Watkins PB, Hoofnagle JH
(2018) J Hepatol 69: 1317-1325
MeSH Terms: Adult, Aged, Alanine Transaminase, Alkaline Phosphatase, Antifungal Agents, Biomarkers, Chemical and Drug Induced Liver Injury, Cholestasis, Female, Follow-Up Studies, HLA-A Antigens, HLA-B14 Antigen, Haplotypes, Humans, Liver, Male, Middle Aged, Molecular Docking Simulation, Polymorphism, Genetic, Prospective Studies, Protein Binding, Terbinafine
Show Abstract · Added March 30, 2020
BACKGROUND & AIMS - Terbinafine is an antifungal agent that has been associated with rare instances of hepatotoxicity. In this study we aimed to describe the presenting features and outcomes of patients with terbinafine hepatotoxicity and to investigate the role of human leukocyte antigen (HLA)-A*33:01.
METHODS - Consecutive high causality cases of terbinafine hepatotoxicity enrolled into the Drug Induced Liver Injury Network were reviewed. DNA samples underwent high-resolution confirmatory HLA sequencing using the Ilumina MiSeq platform.
RESULTS - All 15 patients with terbinafine hepatotoxicity were more than 40 years old (median = 57 years), 53% were female and the median latency to onset was 38 days (range 24 to 114 days). At the onset of drug-induced liver injury, 80% were jaundiced, median serum alanine aminotransferase was 448 U/L and alkaline phosphatase was 333 U/L. One individual required liver transplantation for acute liver failure during follow-up, and 7 of the 13 (54%) remaining individuals had ongoing liver injury at 6 months, with 4 demonstrating persistently abnormal liver biochemistries at month 24. High-resolution HLA genotyping confirmed that 10 of the 11 (91%) European ancestry participants were carriers of the HLA-A*33:01, B*14:02, C*08:02 haplotype, which has a carrier frequency of 1.6% in European Ancestry population controls. One African American patient was also an HLA-A*33:01 carrier while 2 East Asian patients were carriers of a similar HLA type: A*33:03. Molecular docking studies indicated that terbinafine may interact with HLA-A*33:01 and A*33:03.
CONCLUSIONS - Patients with terbinafine hepatotoxicity most commonly present with a mixed or cholestatic liver injury profile and frequently have residual evidence of chronic cholestatic injury. A strong genetic association of HLA-A*33:01 with terbinafine drug-induced liver injury was confirmed amongst Caucasians.
LAY SUMMARY - A locus in the human leukocyte antigen gene (HLA-A*33:01, B*14:02, C*08:02) was significantly overrepresented in Caucasian and African American patients with liver injury attributed to the antifungal medication, terbinafine. These data along with the molecular docking studies demonstrate that this genetic polymorphism is a plausible risk factor for developing terbinafine hepatotoxicity and could be used in the future to help doctors make a diagnosis more rapidly and confidently.
Copyright © 2018 European Association for the Study of the Liver. All rights reserved.
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Mono(2-ethylhexyl) phthalate (MEHP) and mono(2-ethyl-5-oxohexyl) phthalate (MEOHP) but not di(2-ethylhexyl) phthalate (DEHP) bind productively to the peroxisome proliferator-activated receptor γ.
Kratochvil I, Hofmann T, Rother S, Schlichting R, Moretti R, Scharnweber D, Hintze V, Escher BI, Meiler J, Kalkhof S, von Bergen M
(2019) Rapid Commun Mass Spectrom 33 Suppl 1: 75-85
MeSH Terms: Cell Line, Cell Survival, Humans, Hydrogen Deuterium Exchange-Mass Spectrometry, Molecular Docking Simulation, PPAR gamma, Phthalic Acids, Protein Binding
Show Abstract · Added March 21, 2020
RATIONALE - The most frequently occurring phthalate, di(2-ethylhexyl) phthalate (DEHP), causes adverse effects on glucose homeostasis and insulin sensitivity in several cell models and epidemiological studies. However, thus far, there is no information available on the molecular interaction of phthalates and one of the key regulators of the metabolism, the peroxisome proliferator-activated receptor gamma (PPARγ). Since the endogenous ligand of PPARγ, 15-deoxy-delta-12,14-prostaglandin J (15Δ-PGJ ), features structural similarity to DEHP and its main metabolites produced in human hepatic metabolism, mono(2-ethylhexyl) phthalate (MEHP) and mono(2-ethyl-5-oxohexyl) phthalate (MEOHP), we tested the hypothesis of direct interactions between PPARγ and DEHP or its transformation products.
METHODS - Hydrogen/deuterium exchange mass spectrometry (HDX-MS) and docking were conducted to obtain structural insights into the interactions and surface plasmon resonance (SPR) analysis to reveal information about binding levels. To confirm the activation of PPARγ upon ligand binding on the cellular level, the GeneBLAzer® bioassay was performed.
RESULTS - HDX-MS and SPR analyses demonstrated that the metabolites MEHP and MEOHP, but not DEHP itself, bind to the ligand binding pocket of PPARγ. This binding leads to typical activation-associated conformational changes, as observed with its endogenous ligand 15Δ-PGJ . Furthermore, the reporter gene assay confirmed productive interaction. DEHP was inactive up to a concentration of 14 μM, while the metabolites MEHP and MEOHP were active at low micromolar concentrations.
CONCLUSIONS - In summary, this study gives structural insights into the direct interaction of PPARγ with MEHP and MEOHP and shows that the DEHP transformation products may modulate the lipid metabolism through PPARγ pathways.
© 2018 John Wiley & Sons, Ltd.
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