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Title of Journal: J Comput Aided Mol Des

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Abbravation: Journal of Computer-Aided Molecular Design

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Springer Netherlands

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DOI

10.1016/0926-6410(96)00032-8

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1573-4951

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Active site acidic residues and structural analysi

Authors: J Narashima Murthy M Nagaraju G Madhavi Sastry A Raghuram Rao G␣Narahari Sastry
Publish Date: 2006/04/22
Volume: 19, Issue: 12, Pages: 857-870
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Abstract

This study sheds new light on the role of acidic residues present in the active site cavity of human aromatase Eight acidic residues E129 D222 E245 E302 D309 E379 D380 and D476 lining the cavity are identified and studied using comparative modeling docking molecular dynamics as well as statistical techniques The structural environment of these acidic residues is studied to assess the stability of the corresponding carboxylate anions Results indicate that the environment of the residues E245 E302 and D222 is most suitable for carboxylate ion formation in the uncomplexed form However the stability of D309 D222 and D476 anions is seen to increase on complexation to steroidal substrates In particular the interaction between D309 and T310 which assists proton transfer is found to be formed following androgen/norandrogen complexation The residue D309 is found to be clamped in the presence of substrate which is not observed in the case of the other residues although they exhibit changes in properties following substrate binding Information entropic analysis indicates that the residues D309 D222 and D476 have more conformational flexibility compared to E302 and E245 prior to substrate binding Interaction similar to that between D476 and D309 which is expected to assist androgen aromatization is proposed between E302 and E245 The inhibition of aromatase activity by 4hydroxy androstenedione formestane is attributed to a critical hydrogen bond formation between the hydroxy moiety and T310/D309 as well as the large distance from D476 The results corroborate well with earlier site directed mutagenesis studies

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