Abstract 556: CDD: functional insights into orphan GPCRs via subfamily domain architectures
Authors: James S. Song, Noreen R. Gonzales, Roxanne A. Yamashita, Stephen H. Bryant, Aron Marchler-Bauer
Journal: Cancer Research (2017)

Abstract NCBI’s Conserved Domain Database (CDD, https://www.ncbi.nlm.nih.gov/Structure/cdd/cdd.shtml) is a resource that aims at classifying ancient conserved domain families and capturing what is known about their functional diversity. It is a collection of multiple sequence alignments (MSAs) and derived position-specific score matrices (PSSMs). RPS-BLAST allows for the rapid identification of conserved protein domain footprints in protein sequences along with the location of annotated functional sites. CDD is a redundant collection, it imports external domain model collections (Pfam, COGs etc.) and supplement these with manually-curated domain models that are organized into hierarchical classifications, which facilitate annotation of functionally distinct protein families and subfamilies. More recently CDD has been curating information on conserved domain architectures to support functional labeling of proteins that fall into characterized families: SPARCLE (Subfamily Protein ArCHitecture Labeling Engine) is both a curation tool and a public service available at https://www.ncbi.nlm.nih.gov/sparcle. Architecture summaries provide interactive interfaces to lists of proteins that share the same characteristic domain architecture, and to their assigned names, functional labels, and supporting evidence. Here we present the functionally annotated, evolutionary hierarchical classification of the seven-transmembrane G-protein coupled receptors (7TM GPCRs), which includes the largest family of promising therapeutic targets, with more than 140 human orphan GPCRs of unknown function. Across the three kingdoms of life, GPCRs are involved in a wide array of critical physiological processes, and have been implicated in tumor initiation, tumor progression, angiogenesis and metastasis. Orphan subfamilies with unknown endogenous ligand/function are often found to have poor sequence similarity to canonical GPCRs. They have been assigned putative functions with predicted ligand-binding sites, downstream interacting partners, and/or the location of 7TM helices annotated by inference from the molecular and physiological functions of known related GPCR proteins, utilizing more than 25 available 3D-structures, phylogenetic relationships, and the published literature. We hope that this updated classification, together with NCBI’s software tools (Cn3D/CDTree and SPARCLE), will aid researchers in the discovery of molecular therapeutic targets for cancer treatment by providing insights regarding as-yet-unidentified intra-and intermolecular interactions as well as functional mechanisms of GPCR signaling. Acknowledgement: This research was supported by the Intramural Research Program of the National Library of Medicine, NIH. Citation Format: James S. Song, Noreen R. Gonzales, Roxanne A. Yamashita, Stephen H. Bryant, Aron Marchler-Bauer. CDD: functional insights into orphan GPCRs via subfamily domain architectures [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 556. doi:10.1158/1538-7445.AM2017-556