What Makes GPCRs from Different Families Bind to the Same Ligand?
G protein-coupled receptors (GPCRs) are the largest class of cell-surface receptor proteins with important functions in signal transduction and often serve as therapeutic drug targets. With the rapidly growing public data on three dimensional (3D) structures of GPCRs and GPCR-ligand interactions, co...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-06-01
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| Series: | Biomolecules |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2218-273X/12/7/863 |
| _version_ | 1827597897953181696 |
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| author | Kwabena Owusu Dankwah Jonathon E. Mohl Khodeza Begum Ming-Ying Leung |
| author_facet | Kwabena Owusu Dankwah Jonathon E. Mohl Khodeza Begum Ming-Ying Leung |
| author_sort | Kwabena Owusu Dankwah |
| collection | DOAJ |
| description | G protein-coupled receptors (GPCRs) are the largest class of cell-surface receptor proteins with important functions in signal transduction and often serve as therapeutic drug targets. With the rapidly growing public data on three dimensional (3D) structures of GPCRs and GPCR-ligand interactions, computational prediction of GPCR ligand binding becomes a convincing option to high throughput screening and other experimental approaches during the beginning phases of ligand discovery. In this work, we set out to computationally uncover and understand the binding of a single ligand to GPCRs from several different families. Three-dimensional structural comparisons of the GPCRs that bind to the same ligand revealed local 3D structural similarities and often these regions overlap with locations of binding pockets. These pockets were found to be similar (based on backbone geometry and side-chain orientation using APoc), and they correlate positively with electrostatic properties of the pockets. Moreover, the more similar the pockets, the more likely a ligand binding to the pockets will interact with similar residues, have similar conformations, and produce similar binding affinities across the pockets. These findings can be exploited to improve protein function inference, drug repurposing and drug toxicity prediction, and accelerate the development of new drugs. |
| first_indexed | 2024-03-09T03:40:51Z |
| format | Article |
| id | doaj.art-d442add9f8fa45eba691421ced9465e3 |
| institution | Directory Open Access Journal |
| issn | 2218-273X |
| language | English |
| last_indexed | 2024-03-09T03:40:51Z |
| publishDate | 2022-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomolecules |
| spelling | doaj.art-d442add9f8fa45eba691421ced9465e32023-12-03T14:41:43ZengMDPI AGBiomolecules2218-273X2022-06-0112786310.3390/biom12070863What Makes GPCRs from Different Families Bind to the Same Ligand?Kwabena Owusu Dankwah0Jonathon E. Mohl1Khodeza Begum2Ming-Ying Leung3Computational Science Program, The University of Texas at El Paso, El Paso, TX 79968, USAComputational Science Program, The University of Texas at El Paso, El Paso, TX 79968, USABioinformatics Program, The University of Texas at El Paso, El Paso, TX 79968, USAComputational Science Program, The University of Texas at El Paso, El Paso, TX 79968, USAG protein-coupled receptors (GPCRs) are the largest class of cell-surface receptor proteins with important functions in signal transduction and often serve as therapeutic drug targets. With the rapidly growing public data on three dimensional (3D) structures of GPCRs and GPCR-ligand interactions, computational prediction of GPCR ligand binding becomes a convincing option to high throughput screening and other experimental approaches during the beginning phases of ligand discovery. In this work, we set out to computationally uncover and understand the binding of a single ligand to GPCRs from several different families. Three-dimensional structural comparisons of the GPCRs that bind to the same ligand revealed local 3D structural similarities and often these regions overlap with locations of binding pockets. These pockets were found to be similar (based on backbone geometry and side-chain orientation using APoc), and they correlate positively with electrostatic properties of the pockets. Moreover, the more similar the pockets, the more likely a ligand binding to the pockets will interact with similar residues, have similar conformations, and produce similar binding affinities across the pockets. These findings can be exploited to improve protein function inference, drug repurposing and drug toxicity prediction, and accelerate the development of new drugs.https://www.mdpi.com/2218-273X/12/7/863GPCRligandbinding pocket3D structuremotifdocking |
| spellingShingle | Kwabena Owusu Dankwah Jonathon E. Mohl Khodeza Begum Ming-Ying Leung What Makes GPCRs from Different Families Bind to the Same Ligand? Biomolecules GPCR ligand binding pocket 3D structure motif docking |
| title | What Makes GPCRs from Different Families Bind to the Same Ligand? |
| title_full | What Makes GPCRs from Different Families Bind to the Same Ligand? |
| title_fullStr | What Makes GPCRs from Different Families Bind to the Same Ligand? |
| title_full_unstemmed | What Makes GPCRs from Different Families Bind to the Same Ligand? |
| title_short | What Makes GPCRs from Different Families Bind to the Same Ligand? |
| title_sort | what makes gpcrs from different families bind to the same ligand |
| topic | GPCR ligand binding pocket 3D structure motif docking |
| url | https://www.mdpi.com/2218-273X/12/7/863 |
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