Protease activated receptor 2 (PAR2) is an unusual G-protein coupled receptor (GPCR) involved in inflammation and metabolism. It is activated through cleavage of its N-terminus by proteases. The new N-terminus functions as a tethered ligand that folds back and intramolecularly activates PAR2, initiating multiple downstream signaling pathways. The only compounds reported to date to inhibit PAR2 activation are of moderate potency. Three structural models for PAR2 have been constructed based on sequence homology with known crystal structures for bovine rhodopsin, human ORL-1 (also called nociceptin/orphanin FQ receptor), and human PAR1. The three PAR2 model structures were compared and used to predict potential interactions with ligands. Virtual screening for ligands using the Chembridge database, and either ORL-1 or PAR1 derived PAR2 models led to identification of eight new small molecule PAR2 antagonists (IC50 10-100 μM). Notably, the most potent compound 1 (IC50 11 μM) was derived from the less homologous template protein, human ORL-1. The results suggest that virtual screening against multiple homology models of the same GPCR can produce structurally diverse antagonists and that this may be desirable even when some models have less sequence homology with the target protein.
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http://dx.doi.org/10.1021/acs.jcim.5b00087 | DOI Listing |
Heliyon
January 2025
Department of Life and Consumer Sciences, School of Agriculture and Life Sciences, University of South Africa, 1710, Johannesburg, South Africa.
Animal models have become veritable tools in gaining insight into the pathogenesis and progression of several human diseases. These models could range in complexity from to non-human primates. With the aid of these animal models, a lot of new knowledge has been gained about several diseases which otherwise would not have been possible.
View Article and Find Full Text PDFMAbs
December 2025
Biotherapeutics and Genetic Medicine, AbbVie, South San Francisco, CA, USA.
Testing of candidate monoclonal antibody therapeutics in preclinical models is an essential step in drug development. Identification of antibody therapeutic candidates that bind their human targets and cross-react to mouse orthologs is often challenging, especially for targets with low sequence homology. In such cases, surrogate antibodies that bind mouse orthologs must be used.
View Article and Find Full Text PDFProc Natl Acad Sci U S A
January 2025
Faculty of Life Sciences and Medicine, Harbin Institute of Technology Center for Life Sciences, School of Life Science and Technology, Harbin Institute of Technology, Harbin 150001, China.
Lysophosphatidic acid (LPA) exerts its physiological roles through the endothelialdifferentiation gene (EDG) family LPA receptors (LPAR1-3) or the non-EDG family LPA receptors (LPAR4-6). LPAR6 plays crucial roles in hair loss and cancer progression, yet its structural information is very limited. Here, we report the cryoelectron microscopy structure of LPA-bound human LPAR6 in complex with a mini G or G protein.
View Article and Find Full Text PDFInfect Immun
January 2025
Department of Pathology Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
is an opportunistic human pathogen that acquires nutrient metals from the vertebrate host amid infection. During zinc (Zn) scarcity, upregulates the expression of the predicted Zn metallochaperone, . Loss of compromises fitness during Zn deficiency, highlighting its role in this condition.
View Article and Find Full Text PDFJ Biomol Struct Dyn
January 2025
Enzyme and Microbial Technology Research Center, Faculty of Biotechnology and Biomolecular Sciences, Universiti Putra Malaysia, Serdang, Selangor, Malaysia.
The quest for sustainable solutions to plastic pollution has driven research into plastic-degrading enzymes, offering promising avenues for polymer recycling applications. However, enzymes derived from natural sources often exhibit suboptimal thermostability, hindering their industrial viability. Protein engineering techniques have emerged as a powerful approach to enhance the desired properties of these biocatalysts.
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