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Structural basis of negative cooperativity in transthyretin

100%

Neumann P., Cody V., Wojtczak A.

2001

vol. 48

issue 4

867-875

A comparison of the AC and BD binding sites of transthyretin (TTR) was made in terms of the interatomic distances between the Cα 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.

Modeling studies of potato nucleoside triphosphate diphosphohydrolase NTPDase1: an insight into the catalytic mechanism

88%

Kozakiewicz A., Neumann P., Banach M., Komoszyński M., Wojtczak A.

2008

vol. 55

issue 1

141-150

Nucleoside triphosphate diphosphohydrolase - NTPDase1 (apyrase, EC 3.6.1.5) was modeled based on sequence homology. The single polypeptide chain of apyrase is folded into two domains. The putative catalytic site with the apyrase conserved regions (ACR 1-5) is located between these two domains. Modeling confirmed that apyrase belongs to the actin superfamily of proteins. The amino acids interacting with the nucleoside triphosphate substrate and probably involved in the catalyzed hydrolysis were identified. The proposed two-step catalytic mechanism of hydrolysis involves Thr127 and Thr55 as potential nucleophilic factors responsible for the cleavage of the Pγ and Pβ anhydride bonds, respectively. Their action seems to be assisted by Glu170 and Glu78 residues, respectively. The presence of two nucleophiles in the active site of apyrase explains the differences in the hydrolytic activity between apyrases and other enzymes belonging to the NTPDase family.

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2 Acta Biochimica Polonica

1 2008

1 2001

2 Neumann P.

2 Wojtczak A.

1 Banach M.

1 Cody V.

1 Komoszyński M.

1 Kozakiewicz A.

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Structural basis of negative cooperativity in transthyretin

Modeling studies of potato nucleoside triphosphate diphosphohydrolase NTPDase1: an insight into the catalytic mechanism