Comparative Protein Structure Modeling Using MODELLER

Webb, Benjamin; Šali, Andrej

doi:10.1002/0471250953.bi0506s47

Cited by 903 publications

(482 citation statements)

References 216 publications

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“…The alignment was manually edited to remove the amino and carboxy termini which extended past the template structures, and to remove the engineered T4 lysozyme (3PBL) or apocytochrome b562 RIL (BRIL; 5WIU) from the template sequences. MODELLER-9v15 43 was then used to generate (1) a total of 1000 homology models of DRD2, based on the crystal structure of DRD4 in complex with Nemonapride as the template, and (2) a set of 500 models based on the crystal structure of DRD3 in complex with Eticlopride. We then evaluated the models for their ability to enrich known DRD2 ligands over property-matched decoys through docking to the orthosteric binding site, using DOCK 3.7 44 (as detailed below).…”

Section: Methodsmentioning

confidence: 99%

Structure of the D2 dopamine receptor bound to the atypical antipsychotic drug risperidone

Wang

Che

Levit

et al. 2018

Nature

375

431

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Summary Dopamine is a neurotransmitter that has been implicated in processes as diverse as reward, addiction, control of coordinated movement, metabolism and hormonal secretion. Correspondingly, dysregulation of the dopaminergic system has been implicated in diseases ranging from schizophrenia, Parkinson’s disease, depression, attention deficit hyperactivity disorder, nausea and vomiting, among others. Dopamine’s actions are mediated by a family of five G-protein coupled receptors (GPCRs) (viz. D1, D2, D3, D4 and D5)1. The D2 dopamine receptor (DRD2) is the primary target for both typical2 and atypical3,4 antipsychotic drugs, and for Parkinson’s disease drugs. Unfortunately, many drugs targeting DRD2 frequently suffer from serious and potentially life-threatening side effects due to promiscuous activities against related receptors4,5. Accordingly, a molecular understanding of DRD2 structure and function could provide a template for the design of safer and more effective medications. Here we provide the crystal structure of DRD2 in complex with the widely prescribed atypical antipsychotic drug risperidone. The DRD2-risperidone structure reveals an unexpected mode of antipsychotic drug binding to dopamine receptors, and illuminates structural determinants essential for the actions of risperidone and related drugs at DRD2.

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Section: Methodsmentioning

confidence: 99%

Structure of the D2 dopamine receptor bound to the atypical antipsychotic drug risperidone

Wang

Che

Levit

et al. 2018

Nature

375

431

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“…Although the sequence similarity to any β‐propeller with known structure is low, the sequence alignments allowed for a tentative assignment of the WD40 motif for most of the repeats. All homology modeling was performed using MODexplorer (Kosinski et al , 2013), HHpred (Soding et al , 2005), GeneSilico Metaserver (Kurowski & Bujnicki, 2003), and Modeller (Webb & Sali, 2014). …”

Section: Methodsmentioning

confidence: 99%

Structural insights into transcription initiation by yeast RNA polymerase I

et al. 2017

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In eukaryotic cells, RNA polymerase I (Pol I) synthesizes precursor ribosomal RNA (pre‐rRNA) that is subsequently processed into mature rRNA. To initiate transcription, Pol I requires the assembly of a multi‐subunit pre‐initiation complex (PIC) at the ribosomal RNA promoter. In yeast, the minimal PIC includes Pol I, the transcription factor Rrn3, and Core Factor (CF) composed of subunits Rrn6, Rrn7, and Rrn11. Here, we present the cryo‐EM structure of the 18‐subunit yeast Pol I PIC bound to a transcription scaffold. The cryo‐EM map reveals an unexpected arrangement of the DNA and CF subunits relative to Pol I. The upstream DNA is positioned differently than in any previous structures of the Pol II PIC. Furthermore, the TFIIB‐related subunit Rrn7 also occupies a different location compared to the Pol II PIC although it uses similar interfaces as TFIIB to contact DNA. Our results show that although general features of eukaryotic transcription initiation are conserved, Pol I and Pol II use them differently in their respective transcription initiation complexes.

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“…The serpin protein C inhibitor structure (2OL2) (Li and Huntington, 2008) was retrieved from the Protein Data Bank (PDB) (http://www.rcsb.org) and used as a molecular template for AAS19 modeling based on 30% and 53% sequence identity and similarity, respectively. Sequence alignments were generated using the ClustalW algorithm (Larkin et al, 2007) and used as input in the Modeller 9v14 program (Webb and Sali, 2014). Models generated were evaluated using QMEAN4 and PROCHECK to estimate model reliability and predict quality (Morris et al, 1992; Benkert et al, 2008).…”

Section: Methodsmentioning

confidence: 99%

Conserved Amblyomma americanum tick Serpin19, an inhibitor of blood clotting factors Xa and XIa, trypsin and plasmin, has anti-haemostatic functions

Kim

Tirloni

Radulović

et al. 2015

International Journal for Parasitology

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Tick saliva serine protease inhibitors (serpins) facilitate tick blood meal feeding through inhibition of protease mediators of host defense pathways. We previously identified a highly conserved Amblyomma americanum serpin (AAS) 19 that is characterized by its reactive center loop being 100% conserved in ixodid ticks. In this study, biochemical characterization reveals that the ubiquitously transcribed AAS19 is an anti-coagulant protein, inhibiting the activity of five of the eight serine protease blood clotting factors. Pichia pastoris-expressed recombinant (r) AAS19 inhibits the enzyme activity of trypsin, plasmin and blood clotting factors (f) Xa and XIa, with stoichiometry of inhibition estimated at 5.1, 9.4, 23.8 and 28, respectively. Similar to typical inhibitory serpins, rAAS19 forms irreversible complexes with trypsin, fXa and fXIa. At a higher molar excess of rAAS19, fXIIa is inhibited by 82.5%, and thrombin (fIIa), fIXa, chymotrypsin and tryptase are inhibited moderately by 14 – 29%. In anti-hemostatic functional assays, rAAS19 inhibits thrombin but not ADP and cathepsin G activated platelet aggregation, delays clotting in recalcification and thrombin time assays by up to 250 s, and up to 40 s in the activated partial thromboplastin time assay. Given AAS19 high cross-tick species conservation, and specific reactivity of rAAS19 with antibodies to A. americanum tick saliva proteins, we conclude that rAAS19 is a potential candidate for development of a universal tick vaccine.

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Comparative Protein Structure Modeling Using MODELLER

Cited by 903 publications

References 216 publications

Structure of the D2 dopamine receptor bound to the atypical antipsychotic drug risperidone

Structure of the D2 dopamine receptor bound to the atypical antipsychotic drug risperidone

Structural insights into transcription initiation by yeast RNA polymerase I

Conserved Amblyomma americanum tick Serpin19, an inhibitor of blood clotting factors Xa and XIa, trypsin and plasmin, has anti-haemostatic functions

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