3D Structure, Dimerization Modeling, and Lead Discovery by Ligand‐protein Interaction Analysis of p60 Transcription Regulator Protein (p60TRP)

Abstract

The p60 transcription regulator protein (p60TRP) is a basic helix-loop-helix (bHLH) domain-containing neuroprotective protein and a member of the G-protein-coupled receptor (GPCR)-associated sorting protein (GPRASP) family. In the present study, multiple theoretical physico-chemical methods (e.g. Modeller v.9.13, I-TASSER, PROCHECK and ClusPro v2.0 with PIPER) were applied to unveil the three-dimensional (3D) protein structure of the p60TRP homo-dimer protein and explore potential ligand-protein interactions. Our results suggest a Mg(2+) -containing 3D p60TRP dimer protein that potentially interacts with 5-(1-aziridinyl)-2,4-dinitrobenzamide (CB1954) and [2-(3-dodecylimidazolidin-1-yl)-1-phosphonoethyl] phosphonic acid (B73). The discovery of CB1954 and B73 may serve as a potential lead for further drug screening tests to normalize the p60TRP signaling pathway in neurodegenerative diseases. Interference with p60TRP signaling via CB1954/B73-related molecules might be a novel option for modifying neurodegenerative signaling pathways (e.g. RIN1, PP2A, RanBP5, CREB and SYNJ1) to treat various brain diseases.

Identification of a Chemotherapeutic Lead Molecule for the Potential Disruption of the FAM72A-UNG2 Interaction to Interfere with Genome Stability, Centromere Formation, and Genome Editing

“…The crystallographic three-dimensional (3D) protein structure of the FAM72A protein (from Protein Data Bank (PDB) data [ 30 ]) and UNG2 protein (Gene ID: 7374, isoform-2: NP_550433.1, 313 AAs; 1AKZ_A PDB model; DOI: 10.2210/pdb1akz/pdb [ 31 ]) were retrieved from the PDB [ 32 ] with a resolution of 1.55 Å. Compound structures were downloaded from the PubChem database [ 33 ] as described previously [ 30 , 34 , 35 ].…”

“…The UNG2 3D peptide sequence was based on the UNG2 protein sequence (Gene ID: 7374, isoform-2: NP_550433.1, 313 AAs; Uniprot-ID: P13051) and the 1AKZ_A PDB model (DOI: 10.2210/pdb1akz/pdb) [ 31 ] was selected as the template. The obtained template for the N-terminal UNG2 3D peptide structure model (AA 1-313) was then forwarded for UNG2 3D peptide structure modeling with I-TASSER [ 36 , 37 ] and Modeller v9.20 [ 38 , 39 ] software, and Chimera software was used as a graphical interface as described previously [ 34 , 35 , 39 ]. For comparison, we also applied the UNG2 protein sequence to the state-of-the-art machine learning method, AlphaFold (( ), accessed on 3 November 2021) [ 40 , 41 ].…”

Proteomic Atomics Reveals a Distinctive Uracil‐5‐Methyltransferase

“…The 3D structural relationships among the various modeled 3D Pf3D7 U5MTase protein structures were tested, and the stereochemical qualities of obtained U5MTase models were ultimately evaluated with various programs (e. g., PROCHECK, PSVS, and ProSA) to prove the structural quality of the in silico 3D Pf3D7 U5MTase protein structures (including Ramachandran plot, main chain and side chain parameters, and stereochemical quality-check of the by VERIFY3D and ERRAT (http:// nihserver.mbi.ucla.edu/SAVES/)) and to select the best model for further detection of potential ligand binding sites. For further details refer to Pramanik et al, 2015Pramanik et al, , 2016 Finally, the full-length ab initio 3D Pf3D7 U5MTase protein structure model (from Phyre2, with refinement by ModRefiner [10] ) was selected. For further details refer to Pramanik et al, 2015Pramanik et al, , 2016 Further application of COACH, TM-SITE, S-SITE, COFAC-TOR, and ConCavity approaches provided potential ligandbinding sites of the selected 3D U5MTase protein structure model (full length ab initio model with refinement by ModRefiner [10] ) with various molecules based on a BioLiP.…”

“…For further details refer to Pramanik et al, 2015Pramanik et al, , 2016 Finally, the full-length ab initio 3D Pf3D7 U5MTase protein structure model (from Phyre2, with refinement by ModRefiner [10] ) was selected. For further details refer to Pramanik et al, 2015Pramanik et al, , 2016 Further application of COACH, TM-SITE, S-SITE, COFAC-TOR, and ConCavity approaches provided potential ligandbinding sites of the selected 3D U5MTase protein structure model (full length ab initio model with refinement by ModRefiner [10] ) with various molecules based on a BioLiP. [11] The MTiOpenScreen [12] database was applied for chemical library virtual screening.…”

Novel ICT biomedical applications towards precision medicine of chronic diseases

“…Each logo consists of stacks of symbols, and the size of the letter represents its frequency. CDR3 are shown from IMGT positions 105 to 117 [PKH16b].…”