TY  - JOUR
A1  - Schmitt, Dominik R.
A1  - Kuper, Jochen
A1  - Elias, Agnes
A1  - Kisker, Caroline
T1  - The Structure of the TFIIH p34 Subunit Reveals a Von Willebrand Factor A Like Fold
JF  - PLoS ONE
N2  - RNA polymerase II dependent transcription and nucleotide excision repair are mediated by a multifaceted interplay of subunits within the general transcription factor II H (TFIIH). A better understanding of the molecular structure of TFIIH is the key to unravel the mechanism of action of this versatile protein complex within these vital cellular processes. The importance of this complex becomes further evident in the context of severe diseases like xeroderma pigmentosum, Cockayne's syndrome and trichothiodystrophy, that arise from single point mutations in TFIIH subunits. Here we describe the structure of the p34 subunit of the TFIIH complex from the eukaryotic thermophilic fungus Chaetomium thermophilum. The structure revealed that p34 contains a von Willebrand Factor A (vWA) like domain, a fold which is generally known to be involved in protein-protein interactions. Within TFIIH p34 strongly interacts with p44, a positive regulator of the helicase XPD. Putative protein-protein interfaces are analyzed and possible binding sites for the p34-p44 interaction suggested.
KW  - sequence motif analysis
KW  - iodides
KW  - protein-protein interactions
KW  - protein domains
KW  - molecular structure
KW  - electron density
KW  - protein structure
KW  - crystal structure
Y1  - 2014
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-119471
SN  - 1932-6203
VL  - 9
IS  - 7
ER  - 
TY  - JOUR
A1  - Akhoon, Bashir A.
A1  - Singh, Krishna P.
A1  - Varshney, Megha
A1  - Gupta, Shishir K.
A1  - Shukla, Yogeshwar
A1  - Gupta, Shailendra K.
T1  - Understanding the Mechanism of Atovaquone Drug Resistance in Plasmodium falciparum Cytochrome b Mutation Y268S Using Computational Methods
JF  - PLOS ONE
N2  - The rapid appearance of resistant malarial parasites after introduction of atovaquone (ATQ) drug has prompted the search for new drugs as even single point mutations in the active site of Cytochrome b protein can rapidly render ATQ ineffective. The presence of Y268 mutations in the Cytochrome b (Cyt b) protein is previously suggested to be responsible for the ATQ resistance in Plasmodium falciparum (P. falciparum). In this study, we examined the resistance mechanism against ATQ in P. falciparum through computational methods. Here, we reported a reliable protein model of Cyt bc1 complex containing Cyt b and the Iron-Sulphur Protein (ISP) of P. falciparum using composite modeling method by combining threading, ab initio modeling and atomic-level structure refinement approaches. The molecular dynamics simulations suggest that Y268S mutation causes ATQ resistance by reducing hydrophobic interactions between Cyt bc1 protein complex and ATQ. Moreover, the important histidine contact of ATQ with the ISP chain is also lost due to Y268S mutation. We noticed the induced mutation alters the arrangement of active site residues in a fashion that enforces ATQ to find its new stable binding site far away from the wild-type binding pocket. The MM-PBSA calculations also shows that the binding affinity of ATQ with Cyt bc1 complex is enough to hold it at this new site that ultimately leads to the ATQ resistance.
KW  - molecular-dynamics simulations
KW  - HIV-1 protease
KW  - structure prediction
KW  - saccharomyces cerevisiae
KW  - I-tasser
KW  - inhibitors
KW  - binding
KW  - malaria
KW  - complex
KW  - protein-protein interactions
Y1  - 2014
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-114882
VL  - 9
IS  - 10
ER  -