Evolutionary, Structural, And Functional Insights Into The Seven-Transmembrane Gpcr Superfamily Through Ncbi'S Conserved Domain Database

NCBI9s Conserved Domain Database (CDD, http://www.ncbi.nlm.nih.gov/Structure/cdd/cdd.shtml) is a protein classification and annotation resource. It comprises a collection of annotated multiple sequence alignment (MSA) models representing ancient conserved protein domains, basic units of protein function and protein evolution. These MSAs are available as position specific score matrices (PSSMs) for the rapid identification of conserved domains in protein sequences via Reverse Position Specific -BLAST (RPS-BLAST), a variation of the commonly used PSI-BLAST method. CDD includes manually curated domain models that are organized into family hierarchies, which use protein 3D structure information explicitly to refine domain models and provide insights into the relationship between sequence conservation and molecular function. The domain models can be visualized and studied interactively using NCBI9s CDTree/Cn3D software applications. Conserved functional annotations such as ligand-binding sites and/or catalytic active sites are highlighted on protein structures sharing significant homology to the query, thereby pointing out or inferring the underlying mechanism(s) of the protein9s function. Here, we present the functionally annotated, evolutionary hierarchical classification of the seven-transmembrane G-protein coupled receptors (7TM GPCRs), which represent the largest family of membrane-bound proteins across the three kingdoms of life. GPCRs are involved in a wide range of physiological roles including tumor growth and metastasis. With the increasing availability of high-resolution crystal structures of 7TM receptors, we recently undertook a systematic comparative analysis of the highly divergent GPCRs. Orphan GPCR subfamilies, which only contain uncharacterized protein sequences, have putative functions and the location of 7TM helices annotated by inference from the molecular and cellular functions of known related proteins with available 3D structure, and/or based on the available literature. We demonstrate the utility of CDTree/Cn3D in studying the molecular evolution of protein domain families, and in accelerating the pace of GPCR drug discovery by enabling researchers to obtain valuable clues regarding as-yet-unidentified molecular functions and mechanisms. The CDTree/Cn3D software is freely available for download via the CDD website. 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, Aron Marchler-Bauer, Stephen H. Bryant. Evolutionary, structural, and functional insights into the seven-transmembrane GPCR superfamily through NCBI9s Conserved Domain Database. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1090. doi:10.1158/1538-7445.AM2015-1090