Virtual Screening and Bioactivity Modeling for G Protein‐Coupled Receptors

Chan, Wallace K.B.; Wu, Jiansheng; Bell, Eric W.; Zhang, Yang

doi:10.1002/9781119564782.ch12

Cited by 1 publication

(2 citation statements)

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“…10 Another curated database of experimentally-solved and predicted structures is organized in the GPCR-EXP database, which serves as a valuable resource for computational scientists to explore inter and intraprotein interactions, thus facilitating structure-based drug design. 11,12 GPR17, a hybrid GPCR that can bind to extracellular nucleotides and cysteinyl-leukotrienes (CysLT), is emerging as a new promising target for brain damage and repair. 13,14 The extracellular nucleotide (uridine diphosphate [UDP]) and CysLT are two different signaling molecules that bind with P2Y and CysLT families of receptors, respectively.…”

Section: Introductionmentioning

confidence: 99%

“…About 800 GPCRs were identified in humans and classified into six major classes and 69 subfamilies presented in GPCRdb 10 . Another curated database of experimentally‐solved and predicted structures is organized in the GPCR‐EXP database, which serves as a valuable resource for computational scientists to explore inter and intraprotein interactions, thus facilitating structure‐based drug design 11,12 …”

Section: Introductionmentioning

confidence: 99%

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Structural analysis of human G‐protein‐coupled receptor 17 ligand binding sites

Mani

Ramesh

Yli‐Harja

et al. 2023

J of Cellular Biochemistry

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The human G protein coupled membrane receptor (GPR17), the sensor of brain damage, is identified as a biomarker for many neurological diseases. In human brain tissue, GPR17 exist in two isoforms, long and short. While cryo‐electron microscopy technology has provided the structure of the long isoform of GPR17 with Gi complex, the structure of the short isoform and its activation mechanism remains unclear. Recently, we theoretically modeled the structure of the short isoform of GPR17 with Gi signaling protein and identified novel ligands. In the present work, we demonstrated the presence of two distinct ligand binding sites in the short isoform of GPR17. The molecular docking of GPR17 with endogenous (UDP) and synthetic ligands (T0510.3657, MDL29950) found the presence of two distinct binding pockets. Our observations revealed that endogenous ligand UDP can bind stronger in two different binding pockets as evidenced by glide and autodock vina scores, whereas the other two ligand's binding with GPR17 has less docking score. The analysis of receptor−UDP interactions shows complexes' stability in the lipid environment by 100 ns atomic molecular dynamics simulations. The amino acid residues VAL83, ARG87, and PHE111 constitute ligand binding site 1, whereas site 2 constitutes ASN67, ARG129, and LYS232. Root mean square fluctuation analysis showed the residues 83, 87, and 232 with higher fluctuations during molecular dynamics simulation in both binding pockets. Our findings imply that the residues of GPR17's two binding sites are crucial, and their interaction with UDP reveals the protein's hidden signaling and communication properties. Furthermore, this finding may assist in the development of targeted therapies for the treatment of neurological diseases.

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