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Homology modeling with SWISS-MODEL

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

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Homology modeling with SWISS-MODEL

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  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 Modemanually 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- α and ER- • They exhibit overlapping but distinct tissue distribution patterns and differ in their ligand binding affinity and transactivational properties • ER-α 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-α LBD template • First step is obtaining sequence in FASTA format of hER  LBD (1L2J:A) Can be obtained in Protein Data Bank (http://www.rcsb.org/pdb) • Next step is obtaining template structure in agonist conformation (1G50:A) Can be obtained with Search template option in SWISS-MODEL (http://www.expasy.org/swissmod/SWISS-MODEL.html)

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