TSTMP: target selection for structural genomics of human transmembrane proteins

Abstract

The TSTMP database is designed to help the target selection of human transmembrane proteins for structural genomics projects and structure modeling studies. Currently, there are only 60 known 3D structures among the polytopic human transmembrane proteins and about a further 600 could be modeled using existing structures. Although there are a great number of human transmembrane protein structures left to be determined, surprisingly only a small fraction of these proteins have ‘selected’ (or above) status according to the current version the TargetDB/TargetTrack database. This figure is even worse regarding those transmembrane proteins that would contribute the most to the structural coverage of the human transmembrane proteome. The database was built by sorting out proteins from the human transmembrane proteome with known structure and searching for suitable model structures for the remaining proteins by combining the results of a state-of-the-art transmembrane specific fold recognition algorithm and a sequence similarity search algorithm. Proteins were searched for homologues among the human transmembrane proteins in order to select targets whose successful structure determination would lead to the best structural coverage of the human transmembrane proteome. The pipeline constructed for creating the TSTMP database guarantees to keep the database up-to-date. The database is available at http://tstmp.enzim.ttk.mta.hu.

TMCrys: predict propensity of success for transmembrane protein crystallization

“…Although cryo-electron microscopy, acknowledged by Nobel prize this year, is a promising new technique to determine the 3D structures of molecules in their natural environment ( Hite and MacKinnon, 2017 ; Nogales, 2016 ), the selection of targets for structure determination remains one of the greatest question of structural genomics experiments to better avoid long and expensive experimentation with proteins that are not likely to result in resolved structures ( Varga et al , 2017 ). TMPs are usually more challenging due to their special physical-chemical properties.…”

“…TMPs have very special physical-chemical properties as they span the hydrophobic cell and organelle membranes, making the determination of their structures extremely difficult. In a recent work, it was found that among the about 3000 human polytopic TMPs only around 60 ones have an experimentally determined structure that covers all of their membrane regions ( Varga et al , 2017 ).…”

The TMCrys server for supporting crystallization of transmembrane proteins

“…, 2015), however, of all known protein structures only 2% belong to them (Kozma et al. , 2013) and less than a hundred human TMP non-redundant structure is determined (Varga et al. , 2017).…”

The TMCrys server for supporting crystallization of transmembrane proteins

“…They are frequently targeted by pharmaceuticals: a survey found that more than 50% of marketed drugs interact with TMPs (Hopkins and Groom, 2002). Although the human proteome consists of about 25% TMPs (Dobson et al, 2015), however, of all known protein structures only 2% belong to them (Kozma et al, 2013) and less than a hundred human TMP non-redundant structure is determined (Varga et al, 2017). Knowing the structure of TMPs may aid drug development by providing targets for ligand screening and enabling the creation of models for proteins with unknown structures.…”