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Crystal structure of the SH3 domain of human Lyn non-receptor tyrosine kinase.
Berndt S, Gurevich VV, Iverson TM
(2019) PLoS One 14: e0215140
MeSH Terms: Crystallography, X-Ray, Humans, Mutation, Neoplasms, Protein Structure, Tertiary, Recombinant Proteins, src Homology Domains, src-Family Kinases
Show Abstract · Added March 18, 2020
Lyn kinase (Lck/Yes related novel protein tyrosine kinase) belongs to the family of Src-related non-receptor tyrosine kinases. Consistent with physiological roles in cell growth and proliferation, aberrant function of Lyn is associated with various forms of cancer, including leukemia, breast cancer and melanoma. Here, we determine a 1.3 Å resolution crystal structure of the polyproline-binding SH3 regulatory domain of human Lyn kinase, which adopts a five-stranded β-barrel fold. Mapping of cancer-associated point mutations onto this structure reveals that these amino acid substitutions are distributed throughout the SH3 domain and may affect Lyn kinase function distinctly.
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Discovery of Potent Myeloid Cell Leukemia-1 (Mcl-1) Inhibitors That Demonstrate in Vivo Activity in Mouse Xenograft Models of Human Cancer.
Lee T, Christov PP, Shaw S, Tarr JC, Zhao B, Veerasamy N, Jeon KO, Mills JJ, Bian Z, Sensintaffar JL, Arnold AL, Fogarty SA, Perry E, Ramsey HE, Cook RS, Hollingshead M, Davis Millin M, Lee KM, Koss B, Budhraja A, Opferman JT, Kim K, Arteaga CL, Moore WJ, Olejniczak ET, Savona MR, Fesik SW
(2019) J Med Chem 62: 3971-3988
MeSH Terms: Animals, Antineoplastic Agents, Azepines, Binding Sites, Cell Line, Tumor, Cell Survival, Crystallography, X-Ray, Drug Evaluation, Preclinical, Female, Humans, Mice, Mice, Inbred NOD, Mice, SCID, Molecular Dynamics Simulation, Myeloid Cell Leukemia Sequence 1 Protein, Neoplasms, Protein Structure, Tertiary, Small Molecule Libraries, Structure-Activity Relationship, Xenograft Model Antitumor Assays
Show Abstract · Added April 15, 2019
Overexpression of myeloid cell leukemia-1 (Mcl-1) in cancers correlates with high tumor grade and poor survival. Additionally, Mcl-1 drives intrinsic and acquired resistance to many cancer therapeutics, including B cell lymphoma 2 family inhibitors, proteasome inhibitors, and antitubulins. Therefore, Mcl-1 inhibition could serve as a strategy to target cancers that require Mcl-1 to evade apoptosis. Herein, we describe the use of structure-based design to discover a novel compound (42) that robustly and specifically inhibits Mcl-1 in cell culture and animal xenograft models. Compound 42 binds to Mcl-1 with picomolar affinity and inhibited growth of Mcl-1-dependent tumor cell lines in the nanomolar range. Compound 42 also inhibited the growth of hematological and triple negative breast cancer xenografts at well-tolerated doses. These findings highlight the use of structure-based design to identify small molecule Mcl-1 inhibitors and support the use of 42 as a potential treatment strategy to block Mcl-1 activity and induce apoptosis in Mcl-1-dependent cancers.
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20 MeSH Terms
Insight on mutation-induced resistance to anaplastic lymphoma kinase inhibitor ceritinib from molecular dynamics simulations.
He MY, Li WK, Meiler J, Zheng QC, Zhang HX
(2019) Biopolymers 110: e23257
MeSH Terms: Adenosine Triphosphate, Anaplastic Lymphoma Kinase, Binding Sites, Drug Resistance, Neoplasm, Humans, Molecular Dynamics Simulation, Mutagenesis, Site-Directed, Neoplasms, Principal Component Analysis, Protein Kinase Inhibitors, Protein Structure, Tertiary, Pyrimidines, Sulfones
Show Abstract · Added March 21, 2020
Ceritinib, an advanced anaplastic lymphoma kinase (ALK) next-generation inhibitor, has been proved excellent antitumor activity in the treatment of ALK-associated cancers. However, the accumulation of acquired resistance mutations compromise the therapeutic efficacy of ceritinib. Despite abundant mutagenesis data, the structural determinants for reduced ceritinib binding in mutants remains elusive. Focusing on the G1123S and F1174C mutations, we applied molecular dynamics (MD) simulations to study possible reasons for drug resistance caused by these mutations. The MD simulations predict that the studied mutations allosterically impact the configurations of the ATP-binding pocket. An important hydrophobic cluster is identified that connects P-loop and the αC-helix, which has effects on stabilizing the conformation of ATP-binding pocket. It is suggested, in this study, that the G1123S and F1174C mutations can induce the conformational change of P-loop thereby causing the reduced ceritinib affinity and causing drug resistance.
© 2019 Wiley Periodicals, Inc.
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Structural Mechanism of Functional Modulation by Gene Splicing in NMDA Receptors.
Regan MC, Grant T, McDaniel MJ, Karakas E, Zhang J, Traynelis SF, Grigorieff N, Furukawa H
(2018) Neuron 98: 521-529.e3
MeSH Terms: Animals, Cell Line, Female, HEK293 Cells, Humans, Insecta, Protein Splicing, Protein Structure, Secondary, Protein Structure, Tertiary, Receptors, N-Methyl-D-Aspartate, Xenopus laevis
Show Abstract · Added April 10, 2019
Alternative gene splicing gives rise to N-methyl-D-aspartate (NMDA) receptor ion channels with defined functional properties and unique contributions to calcium signaling in a given chemical environment in the mammalian brain. Splice variants possessing the exon-5-encoded motif at the amino-terminal domain (ATD) of the GluN1 subunit are known to display robustly altered deactivation rates and pH sensitivity, but the underlying mechanism for this functional modification is largely unknown. Here, we show through cryoelectron microscopy (cryo-EM) that the presence of the exon 5 motif in GluN1 alters the local architecture of heterotetrameric GluN1-GluN2 NMDA receptors and creates contacts with the ligand-binding domains (LBDs) of the GluN1 and GluN2 subunits, which are absent in NMDA receptors lacking the exon 5 motif. The unique interactions established by the exon 5 motif are essential to the stability of the ATD/LBD and LBD/LBD interfaces that are critically involved in controlling proton sensitivity and deactivation.
Copyright © 2018 Elsevier Inc. All rights reserved.
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Three-dimensional spatial analysis of missense variants in RTEL1 identifies pathogenic variants in patients with Familial Interstitial Pneumonia.
Sivley RM, Sheehan JH, Kropski JA, Cogan J, Blackwell TS, Phillips JA, Bush WS, Meiler J, Capra JA
(2018) BMC Bioinformatics 19: 18
MeSH Terms: Algorithms, Area Under Curve, DNA Helicases, Humans, Lung Diseases, Interstitial, Mutation, Missense, Protein Structure, Tertiary, ROC Curve, Spatial Analysis
Show Abstract · Added March 14, 2018
BACKGROUND - Next-generation sequencing of individuals with genetic diseases often detects candidate rare variants in numerous genes, but determining which are causal remains challenging. We hypothesized that the spatial distribution of missense variants in protein structures contains information about function and pathogenicity that can help prioritize variants of unknown significance (VUS) and elucidate the structural mechanisms leading to disease.
RESULTS - To illustrate this approach in a clinical application, we analyzed 13 candidate missense variants in regulator of telomere elongation helicase 1 (RTEL1) identified in patients with Familial Interstitial Pneumonia (FIP). We curated pathogenic and neutral RTEL1 variants from the literature and public databases. We then used homology modeling to construct a 3D structural model of RTEL1 and mapped known variants into this structure. We next developed a pathogenicity prediction algorithm based on proximity to known disease causing and neutral variants and evaluated its performance with leave-one-out cross-validation. We further validated our predictions with segregation analyses, telomere lengths, and mutagenesis data from the homologous XPD protein. Our algorithm for classifying RTEL1 VUS based on spatial proximity to pathogenic and neutral variation accurately distinguished 7 known pathogenic from 29 neutral variants (ROC AUC = 0.85) in the N-terminal domains of RTEL1. Pathogenic proximity scores were also significantly correlated with effects on ATPase activity (Pearson r = -0.65, p = 0.0004) in XPD, a related helicase. Applying the algorithm to 13 VUS identified from sequencing of RTEL1 from patients predicted five out of six disease-segregating VUS to be pathogenic. We provide structural hypotheses regarding how these mutations may disrupt RTEL1 ATPase and helicase function.
CONCLUSIONS - Spatial analysis of missense variation accurately classified candidate VUS in RTEL1 and suggests how such variants cause disease. Incorporating spatial proximity analyses into other pathogenicity prediction tools may improve accuracy for other genes and genetic diseases.
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9 MeSH Terms
Finding the needle in the haystack: towards solving the protein-folding problem computationally.
Li B, Fooksa M, Heinze S, Meiler J
(2018) Crit Rev Biochem Mol Biol 53: 1-28
MeSH Terms: Algorithms, Animals, Humans, Kinetics, Molecular Dynamics Simulation, Protein Folding, Protein Structure, Tertiary, Proteins, Thermodynamics
Show Abstract · Added March 17, 2018
Prediction of protein tertiary structures from amino acid sequence and understanding the mechanisms of how proteins fold, collectively known as "the protein folding problem," has been a grand challenge in molecular biology for over half a century. Theories have been developed that provide us with an unprecedented understanding of protein folding mechanisms. However, computational simulation of protein folding is still difficult, and prediction of protein tertiary structure from amino acid sequence is an unsolved problem. Progress toward a satisfying solution has been slow due to challenges in sampling the vast conformational space and deriving sufficiently accurate energy functions. Nevertheless, several techniques and algorithms have been adopted to overcome these challenges, and the last two decades have seen exciting advances in enhanced sampling algorithms, computational power and tertiary structure prediction methodologies. This review aims at summarizing these computational techniques, specifically conformational sampling algorithms and energy approximations that have been frequently used to study protein-folding mechanisms or to de novo predict protein tertiary structures. We hope that this review can serve as an overview on how the protein-folding problem can be studied computationally and, in cases where experimental approaches are prohibitive, help the researcher choose the most relevant computational approach for the problem at hand. We conclude with a summary of current challenges faced and an outlook on potential future directions.
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9 MeSH Terms
Improving prediction of helix-helix packing in membrane proteins using predicted contact numbers as restraints.
Li B, Mendenhall J, Nguyen ED, Weiner BE, Fischer AW, Meiler J
(2017) Proteins 85: 1212-1221
MeSH Terms: Algorithms, Amino Acids, Benchmarking, Binding Sites, Membrane Proteins, Models, Molecular, Protein Binding, Protein Conformation, alpha-Helical, Protein Folding, Protein Interaction Domains and Motifs, Protein Structure, Tertiary
Show Abstract · Added April 8, 2017
One of the challenging problems in tertiary structure prediction of helical membrane proteins (HMPs) is the determination of rotation of α-helices around the helix normal. Incorrect prediction of helix rotations substantially disrupts native residue-residue contacts while inducing only a relatively small effect on the overall fold. We previously developed a method for predicting residue contact numbers (CNs), which measure the local packing density of residues within the protein tertiary structure. In this study, we tested the idea of incorporating predicted CNs as restraints to guide the sampling of helix rotation. For a benchmark set of 15 HMPs with simple to rather complicated folds, the average contact recovery (CR) of best-sampled models was improved for all targets, the likelihood of sampling models with CR greater than 20% was increased for 13 targets, and the average RMSD100 of best-sampled models was improved for 12 targets. This study demonstrated that explicit incorporation of CNs as restraints improves the prediction of helix-helix packing. Proteins 2017; 85:1212-1221. © 2017 Wiley Periodicals, Inc.
© 2017 Wiley Periodicals, Inc.
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11 MeSH Terms
Vaccine-Induced Antibodies that Neutralize Group 1 and Group 2 Influenza A Viruses.
Joyce MG, Wheatley AK, Thomas PV, Chuang GY, Soto C, Bailer RT, Druz A, Georgiev IS, Gillespie RA, Kanekiyo M, Kong WP, Leung K, Narpala SN, Prabhakaran MS, Yang ES, Zhang B, Zhang Y, Asokan M, Boyington JC, Bylund T, Darko S, Lees CR, Ransier A, Shen CH, Wang L, Whittle JR, Wu X, Yassine HM, Santos C, Matsuoka Y, Tsybovsky Y, Baxa U, NISC Comparative Sequencing Program, Mullikin JC, Subbarao K, Douek DC, Graham BS, Koup RA, Ledgerwood JE, Roederer M, Shapiro L, Kwong PD, Mascola JR, McDermott AB
(2016) Cell 166: 609-623
MeSH Terms: Adult, Amino Acid Sequence, Antibodies, Neutralizing, Antibodies, Viral, B-Lymphocytes, Epitopes, B-Lymphocyte, Female, Gene Rearrangement, B-Lymphocyte, Heavy Chain, Humans, Immunologic Memory, Influenza A Virus, H5N1 Subtype, Influenza A virus, Influenza Vaccines, Male, Middle Aged, Models, Molecular, Protein Structure, Tertiary, Structure-Activity Relationship, Young Adult
Show Abstract · Added May 3, 2017
Antibodies capable of neutralizing divergent influenza A viruses could form the basis of a universal vaccine. Here, from subjects enrolled in an H5N1 DNA/MIV-prime-boost influenza vaccine trial, we sorted hemagglutinin cross-reactive memory B cells and identified three antibody classes, each capable of neutralizing diverse subtypes of group 1 and group 2 influenza A viruses. Co-crystal structures with hemagglutinin revealed that each class utilized characteristic germline genes and convergent sequence motifs to recognize overlapping epitopes in the hemagglutinin stem. All six analyzed subjects had sequences from at least one multidonor class, and-in half the subjects-multidonor-class sequences were recovered from >40% of cross-reactive B cells. By contrast, these multidonor-class sequences were rare in published antibody datasets. Vaccination with a divergent hemagglutinin can thus increase the frequency of B cells encoding broad influenza A-neutralizing antibodies. We propose the sequence signature-quantified prevalence of these B cells as a metric to guide universal influenza A immunization strategies.
Published by Elsevier Inc.
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19 MeSH Terms
Structural basis for integration of GluD receptors within synaptic organizer complexes.
Elegheert J, Kakegawa W, Clay JE, Shanks NF, Behiels E, Matsuda K, Kohda K, Miura E, Rossmann M, Mitakidis N, Motohashi J, Chang VT, Siebold C, Greger IH, Nakagawa T, Yuzaki M, Aricescu AR
(2016) Science 353: 295-9
MeSH Terms: Animals, Ligands, Long-Term Synaptic Depression, Mice, Nerve Tissue Proteins, Neurogenesis, Protein Multimerization, Protein Precursors, Protein Structure, Tertiary, Purkinje Cells, Receptors, Glutamate, Signal Transduction, Synapses
Show Abstract · Added April 6, 2017
Ionotropic glutamate receptor (iGluR) family members are integrated into supramolecular complexes that modulate their location and function at excitatory synapses. However, a lack of structural information beyond isolated receptors or fragments thereof currently limits the mechanistic understanding of physiological iGluR signaling. Here, we report structural and functional analyses of the prototypical molecular bridge linking postsynaptic iGluR δ2 (GluD2) and presynaptic β-neurexin 1 (β-NRX1) via Cbln1, a C1q-like synaptic organizer. We show how Cbln1 hexamers "anchor" GluD2 amino-terminal domain dimers to monomeric β-NRX1. This arrangement promotes synaptogenesis and is essential for D: -serine-dependent GluD2 signaling in vivo, which underlies long-term depression of cerebellar parallel fiber-Purkinje cell (PF-PC) synapses and motor coordination in developing mice. These results lead to a model where protein and small-molecule ligands synergistically control synaptic iGluR function.
Copyright © 2016, American Association for the Advancement of Science.
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13 MeSH Terms
Structural and Kinetic Analysis of Miscoding Opposite the DNA Adduct 1,N6-Ethenodeoxyadenosine by Human Translesion DNA Polymerase η.
Patra A, Su Y, Zhang Q, Johnson KM, Guengerich FP, Egli M
(2016) J Biol Chem 291: 14134-45
MeSH Terms: Adenosine, Crystallography, X-Ray, DNA Adducts, DNA-Directed DNA Polymerase, Humans, Mass Spectrometry, Protein Structure, Tertiary
Show Abstract · Added March 14, 2018
1,N(6)-Ethenodeoxyadenosine (1,N(6)-ϵdA) is the major etheno lesion formed in the reaction of DNA with epoxides substituted with good leaving groups (e.g. vinyl chloride epoxide). This lesion is also formed endogenously in DNA from lipid oxidation. Recombinant human DNA polymerase η (hpol η) can replicate oligonucleotide templates containing 1,N(6)-ϵdA. In steady-state kinetic analysis, hpol η preferred to incorporate dATP and dGTP, compared with dTTP. Mass spectral analysis of incorporation products also showed preferred purine (A, G) incorporation and extensive -1 frameshifts, suggesting pairing of the inserted purine and slippage before further replication. Five x-ray crystal structures of hpol η ternary complexes were determined, three at the insertion and two at the extension stage. Two insertion complexes revealed incoming non-hydrolyzable dATP or dGTP analogs not pairing with but instead in a staggered configuration relative to 1,N(6)-ϵdA in the anti conformation, thus opposite the 5'-T in the template, explaining the proclivity for frameshift misincorporation. In another insertion complex, dTTP was positioned opposite 1,N(6)-ϵdA, and the adduct base was in the syn conformation, with formation of two hydrogen bonds. At the extension stage, with either an incorporated dA or dT opposite 1,N(6)-ϵdA and 2'-deoxythymidine-5'-[(α,β)-imido]triphosphate opposite the 5'-A, the 3'-terminal nucleoside of the primer was disordered, consistent with the tendency not to incorporate dTTP opposite 1,N(6)-ϵdA. Collectively, the results show a preference for purine pairing opposite 1,N(6)-ϵdA and for -1 frameshifts.
© 2016 by The American Society for Biochemistry and Molecular Biology, Inc.
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7 MeSH Terms