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Homology Modeling of the Human Olfactory Receptor O2D2

Homology Modeling of the Human Olfactory Receptor O2D2. Anurag Sethi. Introduction. Olfactory Receptors are GPCRs. Large repertoire of Olfactory receptors with significant sequence variability in TM 3-6.

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Homology Modeling of the Human Olfactory Receptor O2D2

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  1. Homology Modeling of the Human Olfactory Receptor O2D2 Anurag Sethi

  2. 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 HXXC[DE] 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.

  3. 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.

  4. STAMP alignment of Rhodopsin • Give an example or real life anecdote • Sympathize with the audience’s situation if appropriate

  5. 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.

  6. 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.

  7. Model of O2D2

  8. 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.

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