Modelling the Structure of a Protein Domain (N-terminal of XPB) Linked with Protein Synthesis, DNA Damage Repair, Rare Diseases, Cancer Therapeutics, and Tuberculosis

TL;DR

This paper presents near-complete 3D models of the N-terminal domain of human XPB, revealing its role in transcription, DNA repair, disease mechanisms, and potential tuberculosis therapeutics, using advanced ab-initio modeling with human-in-the-loop techniques.

Contribution

First near-complete 3D models of NTD-hXPB developed using a novel ab-initio protocol incorporating human expertise, providing insights into its biological functions and disease associations.

Findings

NTD-hXPB plays a key role in transcription and DNA repair.

Interactions between NTD-hXPB and protein p52 are significant.

Differences in functionality between human and TB NTD-mXPB were identified.

Abstract

In this work, we develop first near-complete 3D models for NTD-hXPB - the N-terminal protein domain of the human transcription factor XPB. The results are very significant as NTD-hXPB plays a critical role in the synthesis of proteins (specifically transcription) and DNA damage repair (specifically nucleotide excision repair). NTD-hXPB is directly implicated in rare diseases XP-B, XP-CS, and TTD2, whose symptoms include neurodegenerative disorders, premature aging, and decreased fertility. NTDhXPB is also linked to anti-cancer therapies. As a bi-product we derived 3D models of NTD-mXPB - homologue of NTD-hXPB in mycobacterium tuberculosis aka MTB (causative agent of most cases of tuberculosis, which surpassed HIV as #1 infectious disease killer in 2014). These could be potential target for TB therapeutics. Our ab-initio modelling protocol takes advantage of recent powerful advances (prediction of contact residues) in protein structure modeling. Our protocol also includes human in the loop, inspired by the prevailing theory that computational abilities of human minds can be powerfully harnessed in engineering/problem-solving. Using the developed models in this paper, we are able to propose significant insights into (a) the role of NTD-hXPB in the process of transcription and DNA damage repair (specifically NER), (b) the critical interactions of NTD-hXPB with another co-labourer protein p52, (c) diseases associated with NTD-hXPB, and (d) alterations in functionalities between NTD-hXPB (in human) and NTD-mXPB (in TB pathogen).