Homology Modeling of the Human Olfactory Receptor O2D2

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Homology Modeling of the Human Olfactory Receptor
O2D2

• Anurag Sethi

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Introduction

• Olfactory Receptors are GPCRs.
• Large repertoire of Olfactory receptors with
  significant sequence variability in TM 3-6.
• As good metal complexing ligands are better
  odorants, it is postulated that OR might be metal
  binding receptors (binding site in HXXCDE motif
  between TM4 and TM5).
• Homology modeling could be better than previous
  reports
• Using 3 structures rather than a single
  structure.
• Structural alignment and HMM methods used.

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Modeling Alignment

• Templates chosen 1L9H (Bovine Rhodopsin), 1E12
  (Halorhodopsin) and 1JGJ (Sensory Rhodopsin).
• Structural alignment done using STAMP.
• Profile of this was created using HMMer.
• It could recognize all Human Olfactory receptors
  including O2D2 and more than 300 sequences from
  the GPCR super family in the SWISSPROT database.

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STAMP alignment of Rhodopsin

• Give an example or real life anecdote
• Sympathize with the audiences situation if
  appropriate

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Alignment of O2D2 profile

• TMHMM predicts 7 helices but on changing to
  HFFCV, becomes 8 helices.
• O2D2 alignment family using CLUSTAL W and then
  aligned to the Rhodopsin profile using HMMer.
• The TM helices predicted not exactly as TMHMM
  predicts.
• However, TM helices follow the signature of first
  4 helices presented in literature.
• HFFCE comes in middle of 5th helix here.
• After this, the 5th and 6th helices predicted by
  TMHMM becomes 6th and 7th helices based on our
  alignment.

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Comments on Model

• Loops are to be modelled better especially
  start and end.
• It could be that HFFCE is in a transmembrane
  helix throughout and it is a 8 helix bundle.
• We have to model the 8th transmembrane helix
  using constraints.

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Model of O2D2
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Future Work

• HFFCE to be put into the loop position between
  helices 4 and 5 artificially as in insertion and
  then modeled.
• HFFCE could also be put in positions of 4th or
  5th transmembrane helix to simulate the inserted
  state.
• Steered dynamics could be done on system to see
  which is most stable conformation.