Improving homology modeling from low-sequence identity templates in Rosetta: A case study in GPCRs

By Brian Joseph Bender, Brennica Marlow, Jens Meiler. 2020

37 citations recorded by the source corpus.

As sequencing methodologies continue to advance, the availability of protein sequences far outpaces the ability of structure determination. Homology modeling is used to bridge this gap but relies on high-identity templates for accurate model building. G-protein coupled receptors (GPCRs) represent a significant target class for pharmaceutical therapies in which homology modeling could fill the knowledge gap for structure-based drug design. To date, only about 17% of druggable GPCRs have had their structures characterized at atomic resolution. However, modeling of the remaining 83% is hindered by the low sequence identity between receptors. Here we test key inputs in the model building process using GPCRs as a focus to improve the pipeline in two critical ways: Firstly, we use a blended sequence- and structure-based alignment that accounts for structure conservation in loop regions. Secondly, by merging multiple template structures into one comparative model, the best possible template for every region of a target can be used expanding the conformational space sampled in a meaningful way. This optimization allows for accurate modeling of receptors using templates as low as 20% sequence identity, which accounts for nearly the entire druggable space of GPCRs. A model database of all non-odorant GPCRs is made available at www.rosettagpcr.org. Additionally, all protocols are made available with insights into modifications that may improve accuracy at new targets.

Subfields: Cellular and Molecular Neuroscience, Molecular Biology, Radiology, Nuclear Medicine and Imaging, Computational Biology & Bioinformatics

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Citations in the corpus

Multi-State Modeling of G-protein Coupled Receptors at Experimental Accuracy (2021, methodology): “RosettaGPCR performed templatebased modeling using Rosetta to predict GPCR structures in the inactive state.(24) GPCRdb maintains multiple databases related to GPCRs”
GPCRdb in 2021: integrating GPCR sequence, structure and function (2020, positive): “Of all experimental structures that have been released since GPCRdb published its models (23), 37 are in the inactive state but only 21 could be used to benchmark the two model resources because RosettaGPCR’s alignment.fasta files include the target structure D ow nloaded from https://academ ic.oup.”