Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.589439
Title: Computational modelling of G protein-coupled receptors
Author: Taddese, Bruck
Awarding Body: University of Essex
Current Institution: University of Essex
Date of Award: 2012
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Abstract:
G protein-coupled receptors (GPCRs) comprise the most "drugable" family of transmembrane proteins, GPCRs share a common structural template and a general mechanism of signal transduction, but vary greatly in sequence conservation, ligand recognition and function. The current set of class A GPCR crystal structures have facilitated the modelling of class A GPCRs. However, other classes of GPCRs have not been so easy to study. The main focus presented in this thesis is the utilisation of class A GPCR structural information to model medically important GPCRs other than class A GPCRs via molecular modelling. The lack of sequence conservation hampers modelling non-class A GPCRs using class A GPCR crystal structures. A plant GPCR, namely GCR1, has sequence homology to more than one GPCR family (class A, Band E GPCRs) and has been used to align the transmembrane region of class A and B GPCRs. Consequently, we have presented a computational protocol for the identification of putative plant GPCRs that may similarly be used to address the difficult issue of alignment between GPCR families but in this respect only GCR1 was found to be useful. GCR1 is still an orphan GPCR with no known cognate ligand. We first assessed whether GCR 1 was a valid GPCR via homology modelling and molecular dynamics. We found that GCR1 has more similarities to class A and class S GPCRs than was previously acknowledged and further support evidence that GCR1 is a GPCR. Consequently, using the class A - GCR1 - class B alignment, we have produced active and inactive homology models of the CGRP receptor, a prototypical class B GPCR. In conjunction with mutation data, these models were used to identify a number of distinct class B motifs and their class A equivalents for the first time. Finally, molecular dynamic simulations were used to further confirm the role of the class B motifs.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.589439  DOI: Not available
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