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Homology modeling with SWISSMODEL

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... effects are mediated by the oestrogen receptor (ER) a ligand-inducible ... Oestrogen receptor. Two isoforms of ER are known: ER- a and ER ... – PowerPoint PPT presentation

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Title: Homology modeling with SWISSMODEL


1
Homology modeling with SWISS-MODEL
  • Building of hER-beta in agonist conformation
  • Robert Dilis

2
Homology Modeling
  • Homology modeling allows to build the structure
    of a protein when only its amino acid sequence
    and the complete atomic structure of at least one
    other reference protein is known
  • The reference protein must be structurally
    homologous to the model protein being build.
    Structural segments, which are thought to be
    conserved within the family of homologous
    proteins are taken directly from the reference
    protein

3
Homology Modeling with SWISS-MODEL
  • SWISS-MODEL is a fully automated protein
    structure homology modeling server
  • Accessible via the ExPASy Molecular Biology web
    server (http//www.expasy.org/)
  • Also accessible from DeepView (Swiss Pdb-Viewer)
    program
  • DeepView provides manual control during homology
    modeling and tools for analyzing generated models

4
Swiss-model provides two ways of doing homology
modeling
  • First approach mode
    fully automatic procedure http//www.expasy.org
    /swissmod/SWISS-MODEL.html
  • Optimize Mode
    manually optimized
    sequence alignment via DeepView program(Swiss
    Pdb-Viewer)

5
Performing Homology modeling with SWISS-MODEL
  • Search for suitable templates
  • Check sequence identity with target
  • Create ProModII jobs
  • Generate models with ProModII
    This step involves several procedures performed
    by server

6
Performing Homology modeling with SWISS-MODEL
  • Superposition of related 3D-structures
  • Generation of a multiple alignment with the
    sequence to be modeled
  • Generation of a framework for the new sequence
  • Rebuilding lacking loops
  • Completion and correction of backbone
  • Verification of model structure quality and
    packing
  • Energy minimization with Cromos96

7
Oestrogen receptor
  • The sex steroid hormone oestrogen exerts a wide
    variety of tissue-specific effects during growth
    and development
  • These effects are mediated by the oestrogen
    receptor (ER) a ligand-inducible transcription
    factor belonging to the nuclear receptor (NR)
    superfamily
  • Such receptors share a common structural
    organization with distinct domains associated
    with DNA binding and hormone recognition
  • Hormone binding initiates a series of
    conformational changes within the receptor and
    enables ER to interact efficiently with its
    specific DNA response element and to recruit
    components of the transcriptional machinery

8
Oestrogen receptor
  • Two isoforms of ER are known ER- a and ER-?
  • They exhibit overlapping but distinct tissue
    distribution patterns and differ in their ligand
    binding affinity and transactivational properties
  • ER-a and ER-? share modest overall sequence
    identity (47)
  • little homology between N-terminal
    transactivation (AF-1) domains
  • well conserved DNA- and ligand-binding domains
  • The C-terminal ligand-binding domain is
    multifunctional and in addition to a ligand
    binding cavity, contains region for receptor
    dimerization and ligand depended (AF-2)
    transactivation

9
Homology modeling of hER-? LBD in agonist
conformation using hER-a LBD template
  • First step is obtaining sequence in FASTA format
    of hER ? LBD (1L2JA)
    Can be
    obtained in Protein Data Bank (http//www.rcsb.org
    /pdb)
  • Next step is obtaining template structure in
    agonist conformation (1G50A)

    Can be obtained with Search template option in
    SWISS-MODEL (http//www.expasy.org/swissmod/SWISS-
    MODEL.html)
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