[ { "id": "authors:1zaas-8fy25", "collection": "authors", "collection_id": "1zaas-8fy25", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20210127-083243229", "type": "book_section", "title": "Structural Variation and Odorant Binding for Olfactory Receptors Selected from the Six Major Subclasses of the OR Phylogenetic Tree", "book_title": "Computational Materials, Chemistry, and Biochemistry: From Bold Initiatives to the Last Mile", "author": [ { "family_name": "Malinska", "given_name": "Maura", "orcid": "0000-0002-7138-7041", "clpid": "Malinska-Maura" }, { "family_name": "Kim", "given_name": "Soo-Kyung", "orcid": "0000-0002-4498-5441", "clpid": "Kim-Soo-Kyung" }, { "family_name": "Goddard", "given_name": "William, III", "orcid": "0000-0003-0097-5716", "clpid": "Goddard-W-A-III" }, { "family_name": "Ashok", "given_name": "Manasa", "clpid": "Ashok-Manasa" } ], "contributor": [ { "family_name": "Shankar", "given_name": "Sadasivan", "clpid": "Shankar-Sadasivan" }, { "family_name": "Muller", "given_name": "Richard", "clpid": "Muller-Richard" }, { "family_name": "Dunning", "given_name": "Thom", "clpid": "Dunning-Thom-H" }, { "family_name": "Chen", "given_name": "Guan Hua", "clpid": "Chen-Guan-Hua" } ], "abstract": "To provide some insight on odorant recognition, we partitioned the 398 human olfactory receptors (OR) into six subclasses based on the phylogenetic tree and predicted the 3D structure and binding site for the family head of each subclass. We used the GPCR Ensemble of Structures in Membrane BiLayer Environment (GEnSeMBLE) method that samples 10 trillion combinations of helix tilts and rotations to select an ensemble of the 25 most stable 7-helix packings. We found that the ensembles for the OR in all 6 subclasses exhibit the TM1-2-7 coupling characteristic of Class A G protein-coupled receptors (GPCRs). In many cases of tetrapod subclasses, the conserved R3.50:E6.30 TM3-TM6 coupling in the inactive GPCRs is replaced with D(E)3.39:H6.40 and D3.49:R(K)6.30 interactions. We found a different pattern for the fish-like class I, where D3.49 couples with residues in TM4 (R4.44 for O52D1-I and Q4.41/K4.38 for O52B6-I) instead of TM6. A variety of residues lining the binding site are involved depending on the ligand: Q103^(3.28) and N282^(7.39( for O52D1-I, Y91^(2.53) for O11H6-II, Q97^(3.28) for OR4Q2-III, S272^(7.35) for OR7D4-IV, S206^(5.43) for OR2J3-V, and T249^(6.45) for OR5P3-VI. Here, we provide the structures for the top25 for all 11 ORs, including the structures with ligands.", "doi": "10.1007/978-3-030-18778-1_37", "isbn": "978-3-030-18777-4", "publisher": "Springer International Publishing", "place_of_publication": "Cham", "publication_date": "2021-01-26", "pages": "855-925" }, { "id": "authors:rrpmn-5xr22", "collection": "authors", "collection_id": "rrpmn-5xr22", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20170130-142028601", "type": "book_section", "title": "Molecular-Docking-Based Drug Design and Discovery: Rational Drug Design for the Subtype Selective GPCR Ligands", "author": [ { "family_name": "Kim", "given_name": "Soo-Kyung", "orcid": "0000-0002-4498-5441", "clpid": "Kim-Soo-Kyung" }, { "family_name": "Goddard III", "given_name": "William A.", "orcid": "0000-0003-0097-5716", "clpid": "Goddard-W-A-III" } ], "contributor": [ { "family_name": "Dastmalchi", "given_name": "Siavoush", "clpid": "Dastmalchi-S" }, { "family_name": "Hamzeh-Mivehroud", "given_name": "Maryam", "clpid": "Hamzeh-Mivehroud-M" }, { "family_name": "Sokouti", "given_name": "Babak", "clpid": "Sokouti-B" } ], "abstract": "Currently 30-50% of drug targets are G Protein-Coupled Receptors (GPCRs). However, the clinical useful drugs for targeting GPCR have been limited by the lack of subtype selectivity or efficacy, leading to undesirable side effects. To develop subtype-selective GPCR ligands with desired molecular properties, better understanding is needed of the pharmacophore elements and of the binding mechanism required for subtype selectivity. To illustrate these issues, we describe here three successful applications to understand the binding mechanism associated with subtype selectivity: 5-HT2B (5-Hydroxytryptamine, 5-HT) serotonin receptor (HT2BR), H3 histamine receptor (H3HR) and A3 adenosine receptor (A3AR). The understanding of structure-function relationships among individual types and subtypes of GPCRs gained from such computational predictions combined with experimental validation and testing is expected the development of new highly selective and effective ligands to address such diseases while minimizing side-effects.", "doi": "10.4018/978-1-5225-0362-0.ch006", "publisher": "Medical Information Science Reference", "publication_date": "2016" }, { "id": "authors:rkpra-2q209", "collection": "authors", "collection_id": "rkpra-2q209", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130128-104922610", "type": "book_section", "title": "Conformational Ensemble View of G Protein-Coupled Receptors and the Effect of Mutations and Ligand Binding", "book_title": "G Protein Coupled Receptors \u2014 Structure", "author": [ { "family_name": "Abrol", "given_name": "Ravinder", "orcid": "0000-0001-7333-6793", "clpid": "Abrol-R" }, { "family_name": "Kim", "given_name": "Soo-Kyung", "orcid": "0000-0002-4498-5441", "clpid": "Kim-Soo-Kyung" }, { "family_name": "Bray", "given_name": "Jenelle K.", "clpid": "Bray-J-K" }, { "family_name": "Trzaskowski", "given_name": "Bartosz", "clpid": "Trzaskowski-B" }, { "family_name": "Goddard", "given_name": "William A., III", "orcid": "0000-0003-0097-5716", "clpid": "Goddard-W-A-III" } ], "contributor": [ { "family_name": "Conn", "given_name": "P. Michael", "clpid": "Conn-P-M" } ], "abstract": "G protein-coupled receptors (GPCRs) are integral membrane proteins that can convert an extracellular signal into multiple intracellular signaling processes. This pleiotropy of GPCRs is enabled by their structural flexibility manifested in thermally accessible multiple conformations, each of which may be capable of activating a different signaling cascade inside the cell (Kenakin & Miller, 2010). Different subsets of conformations can be potentially stabilized through mutations, or binding to various ligands (inverse agonists, antagonists, and agonists), or binding to G proteins, etc. Structure determination efforts have led to a small subset of these receptors being crystallized in one or two distinct conformations, but computational methods can predict an ensemble of conformations that characterize the full thermodynamic landscape of the receptor. Mutations in the receptor or binding of ligands can modulate this energy landscape, by stabilizing a unique set of conformations under different conditions, which may correspond to a specific downstream physiological function. These studies can provide testable hypotheses on the structural basis of GPCR activation and functional selectivity.", "doi": "10.1016/B978-0-12-391861-1.00002-2", "isbn": "9780123918611", "publisher": "Academic Press", "place_of_publication": "Oxford", "publication_date": "2013", "pages": "31-48" } ]