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1

Comparison of binding interactions of dibromoflavonoids with transthyretin

100%
Muziol T., Cody V., Wojtczak A.
Acta Biochimica Polonica
|
2001
|
tom 48
|
nr 4
The crystal structure of rat transthyretin (rTTR) complex with the dibromoflavone EMD21388 was determined to 2.3 A resolution and refined to R = 0.203 and Rfree = 0.288. Two different orientations of EMD21388, which differ in the channel penetra tion by 1.6 A, were found in the A/C binding site of rTTR. The single ligand position observed in the B/D site is intermediate between the two positions found in the A/C site. The position of the dibromoflavone in the B/D site is similar to that reported for dibromoaurone in human TTR. The bromine atoms of EMD21388 form strong inter­actions in the P3 and P3' pockets of rTTR. Due to the different molecular architec­tures of both ligands, dibromoflavone forms only one interaction with Lys-15 near the channel entrance, while direct interactions with the pair of Lys-15 were reported for dibromoaurone. The C3* methyl group of EMD21388 mediates the bridging interac­tions between two TTR subunits in the P2 pockets. The interactions of the O2* hydroxyl group of dibromoaurone with the Thr-119 side chain in the P3 pockets are not matched by similar interactions in EMD21388. Both these alternative interac­tions can explain the competitive binding of 3 ,5 -dibromoflavonoids to transthyretin.
2

Structural basis of negative cooperativity in transthyretin

100%
Neumann P., Cody V., Wojtczak A.
Acta Biochimica Polonica
|
2001
|
tom 48
|
nr 4
A comparison of the AC and BD binding sites of transthyretin (TTR) was made in terms of the interatomic distances between the Ca atoms of equivalent amino acids, measured across the tetramer channel in each binding site. The comparison of the channel diameter for apo TTR from different sources revealed that in the unliganded transthyretin tetramers the distances between the A, D and H β-strands are consis­tently larger, while the distances between the G β-strands are smaller in one site than in the other. These differences might be described to have a 'wave' character. An anal­ogous analysis performed for transthyretin complexes reveals that the shape of the plot is similar, although the amplitudes of the changes are smaller. The analysis leads us to a model of the changes in the binding sites caused by ligand binding. The se­quence of events includes ligand binding in the first site, followed by a slight collapse of this site and concomitant opening of the second site, binding of the second molecule and collapse of the second site. The following opening of the first, already occupied site upon ligand binding in the second site is smaller because of the bridging interac­tions already formed by the first ligand. This explains the negative cooperativity (NC) effect observed for many ligands in transthyretin.
3

Computer modelling studies of the structural role of NADPH binding to active site mutants of human dihydrofolate reductase in complex with piritrexim

100%
Nowak W., Cody V., Wojtczak A.
Acta Biochimica Polonica
|
2001
|
tom 48
|
nr 4
Dihydrofolate reductase (DHFR, EC 1.5.1.3) is one of the enzymes active in the fo­late cycle which plays an important role in DNA synthesis. Inhibition of DHFR is a key element in the treatment of many diseases, including cancer and AIDS related infec­tions. A search for new selective inhibitors is motivated by the resistance to common drugs observed in the course of treatment. In this paper, results of a detailed com­puter analysis of human DHFR interactions with the lipophilic inhibitor piritrexim (PTX) are presented. It was found that the NADPH cofactor contributes 30% of the to­tal PTX-enzyme interaction energy. Substitution of the highly conserved Glu30 with alanine does not lead to the release of the inhibitor from the hDHFR pocket. The im­portant L22F point mutation does affect PTX orientation but does not change the binding energy. Simulations of the dynamics of binary hDHFR-PTX complexes were performed with the use of Extensible Systematic Force Field (ESFF) and the results in­dicate structural changes in the enzyme induced by NADPH binding.
4

Complex of rat transthyretin with tetraiodothyroacetic acid refined at 2.1 and 1.8 A resolution

88%
Muziol T., Cody V., Luft J. R., Pangborn W., Wojtczak A.
Acta Biochimica Polonica
|
2001
|
tom 48
|
nr 4
The crystal structure of rat transthyretin (rTTR) complex with 3,5,3' ,5' -tetra­iodothyroacetic acid (T4Ac) was determined at 1.8 A resolution with low temperature synchrotron data collected at CHESS. The structure was refined to R = 0.207 and Rfree = 0.24 with the use of 8-1.8 A data. The additional 8000 reflections from the in­complete 2.1-1.8 data shell, included in the refinement, reduced the Rfree index by 1.3%. Structure comparison with the model refined against the complete 8-2.1 A data revealed no differences in the ligand orientation and the conformation of the polypeptide chain in the core regions. However, the high-resolution data included in the refinement improved the model in the flexible regions poorly defined with the lower resolution data. Also additional sixteen water molecules were found in the dif­ference map calculated with the extended data. The structure revealed both forward and reverse binding of tetraiodothyroacetic acid in one binding site and two modes of forward ligand binding in the second site, with the phenolic iodine atoms occupying different sets of the halogen binding pockets.
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