DR-SIP: protocols for higher order structure modeling with distance restraints- and cyclic symmetry-imposed packing

Chan, Justin; Zou, Jinhao; Ortiz, Christopher Llynard; Chien, Chi-Hong Chang; Pan, Rong-Long; Yang, Lee‐Wei

doi:10.1093/bioinformatics/btz579

Cited by 1 publication

(1 citation statement)

References 56 publications

(57 reference statements)

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“…The reliable 3D structure determination in most of homo-oligomeric transmembrane proteins (HoTPs) depends on the protocol including cyclic symmetry (Cn symmetry). Moreover, ∼97% of 118 X-ray crystallographically solved structures of homo-oligomeric transmembrane proteins are Cn symmetric which highlights that the prevalence of Cn symmetric HoTPs and the benefits of integrating geometry restraints in quaternary structure determination [ 12 ]. Hence, we utilized SymmDock predicted homodimers of TPO proteins for the analyses [ 13 ].…”

Section: Methodsmentioning

confidence: 99%

Investigation of the impact of nonsynonymous mutations on thyroid peroxidase dimer

Begum,

Mahtarin,

Ahmed

et al. 2023

PLoS ONE

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Congenital hypothyroidism is one of the most common preventable endocrine disorders associated with thyroid dysgenesis or dyshormonogenesis. Thyroid peroxidase (TPO) gene defect is mainly responsible for dyshormonogenesis; a defect in the thyroid hormone biosynthesis pathway. In Bangladesh, there is limited data regarding the genetic etiology of Congenital Hypothyroidism (CH). The present study investigates the impact of the detected mutations (p.Ala373Ser, and p.Thr725Pro) on the TPO dimer protein. We have performed sequential molecular docking of H2O2 and I- ligands with both monomers of TPO dimer to understand the iodination process in thyroid hormone biosynthesis. Understanding homodimer interactions at the atomic level is a critical challenge to elucidate their biological mechanisms of action. The docking results reveal that mutations in the dimer severely disrupt its catalytic interaction with essential ligands. Molecular dynamics simulation has been performed to validate the docking results, thus realizing the consequence of the mutation in the biological system’s mimic. The dynamics results expose that mutations destabilize the TPO dimer protein. Finally, principal component analysis exhibits structural and energy profile discrepancies in wild-type and mutant dimers. The findings of this study highlight that the mutations in TPO protein can critically affect the dimer structure and loss of enzymatic activity is persistent. Other factors also might influence the hormone synthesis pathway, which is under investigation.

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Section: Methodsmentioning

confidence: 99%