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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
A scheme of 7TMH fold of Rhodopsin-like class of GPCRs.Here, we superposed crystal structures of three GPCRs of varied loop conformations: chemokine CXCR4 (PDB id: 3ODU), adrenergic β2AR (2RH1) and adenosine A2AR receptors (2YDV). Except for variety of loop conformations, GPCR structures differ by kinks in TM helices, e.g., in TMH1 (dark blue) and TMH5 (orange), and the length of TM helices, e.g., of TMH7 (dark red).
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pone-0056742-g001: A scheme of 7TMH fold of Rhodopsin-like class of GPCRs.Here, we superposed crystal structures of three GPCRs of varied loop conformations: chemokine CXCR4 (PDB id: 3ODU), adrenergic β2AR (2RH1) and adenosine A2AR receptors (2YDV). Except for variety of loop conformations, GPCR structures differ by kinks in TM helices, e.g., in TMH1 (dark blue) and TMH5 (orange), and the length of TM helices, e.g., of TMH7 (dark red).

Mentions: Although all GPCRs are believed to share the same 7 transmembrane helices fold (7TMH) they significantly differ in loop conformations, presence of helical kinks or other deformations of TM helices represented by bulges (see Figure 1). Even if structural differences between two GPCRs are negligible as between β1AR and β2AR receptors a few differently oriented amino acids side chains might completely change the binding mode of endogenous or exogenous ligands. For those reasons structure prediction of GPCRs is considered to be a challenge. In general, computational methods based on sequence homology performed much better in GPCR structure prediction than the de novo methods, as it was proved by the last GPCRDock 2010 competition [8]. In general, due to the relatively low number of membrane proteins in PDB, their de novo structure prediction is less accurate and thus less common than in the case of globular proteins. Notable exceptions are two recently developed methods: Rosetta-membrane [9] and FILM3 [10] (see Table 1). Another interesting example is the protein folding de novo based on evolutionary-based constraints (EVfold), recently tested on membrane proteins [11].


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)

A scheme of 7TMH fold of Rhodopsin-like class of GPCRs.Here, we superposed crystal structures of three GPCRs of varied loop conformations: chemokine CXCR4 (PDB id: 3ODU), adrenergic β2AR (2RH1) and adenosine A2AR receptors (2YDV). Except for variety of loop conformations, GPCR structures differ by kinks in TM helices, e.g., in TMH1 (dark blue) and TMH5 (orange), and the length of TM helices, e.g., of TMH7 (dark red).
© Copyright Policy
Related In: Results  -  Collection

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

pone-0056742-g001: A scheme of 7TMH fold of Rhodopsin-like class of GPCRs.Here, we superposed crystal structures of three GPCRs of varied loop conformations: chemokine CXCR4 (PDB id: 3ODU), adrenergic β2AR (2RH1) and adenosine A2AR receptors (2YDV). Except for variety of loop conformations, GPCR structures differ by kinks in TM helices, e.g., in TMH1 (dark blue) and TMH5 (orange), and the length of TM helices, e.g., of TMH7 (dark red).
Mentions: Although all GPCRs are believed to share the same 7 transmembrane helices fold (7TMH) they significantly differ in loop conformations, presence of helical kinks or other deformations of TM helices represented by bulges (see Figure 1). Even if structural differences between two GPCRs are negligible as between β1AR and β2AR receptors a few differently oriented amino acids side chains might completely change the binding mode of endogenous or exogenous ligands. For those reasons structure prediction of GPCRs is considered to be a challenge. In general, computational methods based on sequence homology performed much better in GPCR structure prediction than the de novo methods, as it was proved by the last GPCRDock 2010 competition [8]. In general, due to the relatively low number of membrane proteins in PDB, their de novo structure prediction is less accurate and thus less common than in the case of globular proteins. Notable exceptions are two recently developed methods: Rosetta-membrane [9] and FILM3 [10] (see Table 1). Another interesting example is the protein folding de novo based on evolutionary-based constraints (EVfold), recently tested on membrane proteins [11].

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