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Biography

Stanislav Engel, Ph.D., now is an Assistant Professor in the Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, The National Institute for Biotechnology, Ben-Gurion University in the Negev, Beer-Sheva, Israel. He got his B Sc in biochemistry, M Sc and Ph.D. in biochemistry and biotechnology engineering at the Ben-Gurion University in the Negev. Currently, Dr. Stanislav Engel’ researches focus on the understanding the structural basis of “protein misfolding” diseases, such as ALS, and structure-based drug discovery.

Abstract

Dissecting G protein-coupled receptors (GPCR) signaling in terms of the pathways being activated will boost our understanding of the molecular fundamentals of hormone action. The structural determinants governing the selectivity of GPCR/G protein coupling, however, remain obscure. The selectivity of GPCR/G protein recognition appears to be determined by both specific inter-residue interactions and features related to the overall 3D conformation of the ICD. It appears, therefore, that to elucidate the fundamentals of the selectivity of GPCR/G protein recognition, a comprehensive analysis of the structure-activity relationships of multiple GPCR complexes with different G protein isoforms is required. However, enormous technical difficulties associated with the isolation of functional receptors in quantities required for direct structural studies effectively impede progress in the field. Methodology: We constructed the functional mimetics of the intracellular domain (ICD) of a model GPCR - thyrotropin receptor (TSHR), based on a unique scaffold, 6-Helix, an artificial protein that was derived from the elements of the trimer-of-hairpins structure of HIV gp41 and represents a bundle of six a-helices. Findings: The 6-Helix scaffold, which endowed the substituted TSHR ICD elements with spatial constraints analogous to those, found in native receptors, enabled the reconstitution of a microdomain comprising the intracellular loops ICL-2 and ICL-3, which is capable of binding and activating Ga-(s). Conclusion & Significance: By using a soluble scaffold, which furnishes peptides derived from the GPCR ICD with spatial constraints similar to those, found in native receptors, the reconstitution of a native-like G protein-recognition epitope can be facilitated. The 6-Helix-based mimetics could be used as a platform to study the molecular basis of GPCR/G protein recognition. Such knowledge could lead to the development of novel therapeutic strategies for GPCR-related disorders by targeting the GPCR/G protein interfaces and help counteract cellular dysfunctions via focused tuning of GPCR signaling.