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Towards improved quality of GPCR models by usage of multiple templates and profile-profile comparison.

Latek D, Pasznik P, Carlomagno T, Filipek S - PLoS ONE (2013)

Bottom Line: Usage of multiple templates and generation of alignments based on sequence profiles may increase the rate of success in difficult cases of comparative modeling in which the sequence similarity between GPCRs is exceptionally low.In particular, GPCRM is the first GPCR structure predictor incorporating two distinct loop modeling techniques: Modeller and Rosetta together with the filtering of models based on the Z-coordinate.We also provide a database of precomputed GPCR models of the human receptors from that class.

View Article: PubMed Central - PubMed

Affiliation: International Institute of Molecular and Cell Biology, Warsaw, Poland. dlatek@iimcb.gov.pl

ABSTRACT

Unlabelled: G-protein coupled receptors (GPCRs) are targets of nearly one third of the drugs at the current pharmaceutical market. Despite their importance in many cellular processes the crystal structures are available for less than 20 unique GPCRs of the Rhodopsin-like class. Fortunately, even though involved in different signaling cascades, this large group of membrane proteins has preserved a uniform structure comprising seven transmembrane helices that allows quite reliable comparative modeling. Nevertheless, low sequence similarity between the GPCR family members is still a serious obstacle not only in template selection but also in providing theoretical models of acceptable quality. An additional level of difficulty is the prediction of kinks and bulges in transmembrane helices. Usage of multiple templates and generation of alignments based on sequence profiles may increase the rate of success in difficult cases of comparative modeling in which the sequence similarity between GPCRs is exceptionally low. Here, we present GPCRM, a novel method for fast and accurate generation of GPCR models using averaging of multiple template structures and profile-profile comparison. In particular, GPCRM is the first GPCR structure predictor incorporating two distinct loop modeling techniques: Modeller and Rosetta together with the filtering of models based on the Z-coordinate. We tested our approach on all unique GPCR structures determined to date and report its performance in comparison with other computational methods targeting the Rhodopsin-like class. We also provide a database of precomputed GPCR models of the human receptors from that class.

Availability: GPCRM SERVER AND DATABASE: http://gpcrm.biomodellab.eu.

Show MeSH
The GPCRM modeling pipeline.A human intervention is possible in the ‘Advanced’ user mode at the steps indicated by asterisks.
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pone-0056742-g002: The GPCRM modeling pipeline.A human intervention is possible in the ‘Advanced’ user mode at the steps indicated by asterisks.

Mentions: The concept of model building from multiple templates was studied extensively by Larsson et al. [31] on a large globular protein data set (CASP7 and Wallner's benchmark models) and proved to be successful as long as 2 or 3 templates were used instead of one. On average, further increasing of the number of templates did not improve the protein model and sometimes caused its disruption due to significant structural differences between templates impossible to average by Modeller. GPCRs share a similar 7TM fold which facilitates an efficient averaging of coordinates. For that reason, in the GPCRM pipeline (see Figure 2) a protein model can be built from as many templates as are available using an iterative reconciliation of alignments. What is more, the final protein model is not a sum of structural fragments picked from various templates like in SSFE, but an average structure built on the given set of templates. Such an approach is especially valuable when the selection of the single template is difficult due to low sequence similarity between a modeled GPCR and available templates.


Towards improved quality of GPCR models by usage of multiple templates and profile-profile comparison.

Latek D, Pasznik P, Carlomagno T, Filipek S - PLoS ONE (2013)

The GPCRM modeling pipeline.A human intervention is possible in the ‘Advanced’ user mode at the steps indicated by asterisks.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3585245&req=5

pone-0056742-g002: The GPCRM modeling pipeline.A human intervention is possible in the ‘Advanced’ user mode at the steps indicated by asterisks.
Mentions: The concept of model building from multiple templates was studied extensively by Larsson et al. [31] on a large globular protein data set (CASP7 and Wallner's benchmark models) and proved to be successful as long as 2 or 3 templates were used instead of one. On average, further increasing of the number of templates did not improve the protein model and sometimes caused its disruption due to significant structural differences between templates impossible to average by Modeller. GPCRs share a similar 7TM fold which facilitates an efficient averaging of coordinates. For that reason, in the GPCRM pipeline (see Figure 2) a protein model can be built from as many templates as are available using an iterative reconciliation of alignments. What is more, the final protein model is not a sum of structural fragments picked from various templates like in SSFE, but an average structure built on the given set of templates. Such an approach is especially valuable when the selection of the single template is difficult due to low sequence similarity between a modeled GPCR and available templates.

Bottom Line: Usage of multiple templates and generation of alignments based on sequence profiles may increase the rate of success in difficult cases of comparative modeling in which the sequence similarity between GPCRs is exceptionally low.In particular, GPCRM is the first GPCR structure predictor incorporating two distinct loop modeling techniques: Modeller and Rosetta together with the filtering of models based on the Z-coordinate.We also provide a database of precomputed GPCR models of the human receptors from that class.

View Article: PubMed Central - PubMed

Affiliation: International Institute of Molecular and Cell Biology, Warsaw, Poland. dlatek@iimcb.gov.pl

ABSTRACT

Unlabelled: G-protein coupled receptors (GPCRs) are targets of nearly one third of the drugs at the current pharmaceutical market. Despite their importance in many cellular processes the crystal structures are available for less than 20 unique GPCRs of the Rhodopsin-like class. Fortunately, even though involved in different signaling cascades, this large group of membrane proteins has preserved a uniform structure comprising seven transmembrane helices that allows quite reliable comparative modeling. Nevertheless, low sequence similarity between the GPCR family members is still a serious obstacle not only in template selection but also in providing theoretical models of acceptable quality. An additional level of difficulty is the prediction of kinks and bulges in transmembrane helices. Usage of multiple templates and generation of alignments based on sequence profiles may increase the rate of success in difficult cases of comparative modeling in which the sequence similarity between GPCRs is exceptionally low. Here, we present GPCRM, a novel method for fast and accurate generation of GPCR models using averaging of multiple template structures and profile-profile comparison. In particular, GPCRM is the first GPCR structure predictor incorporating two distinct loop modeling techniques: Modeller and Rosetta together with the filtering of models based on the Z-coordinate. We tested our approach on all unique GPCR structures determined to date and report its performance in comparison with other computational methods targeting the Rhodopsin-like class. We also provide a database of precomputed GPCR models of the human receptors from that class.

Availability: GPCRM SERVER AND DATABASE: http://gpcrm.biomodellab.eu.

Show MeSH