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Current Computer-Aided Drug Design

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ISSN (Print): 1573-4099
ISSN (Online): 1875-6697

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Research Article

New Insights into the Binding Mechanism of Co-regulator BUD31 to AR AF2 Site: Structural Determination and Analysis of the Mutation Effect

Author(s): Tianqing Song and Jiazhong Li*

Volume 16, Issue 1, 2020

Page: [45 - 53] Pages: 9

DOI: 10.2174/1573409915666190502153307

Price: $65

Abstract

Introduction: Androgen Receptor (AR) plays a pivotal role in the development of male sex and contributes to prostate cancer growth. Different from other nuclear receptors that bind to the co-regulator LxxLL motif in coregulator peptide interaction, the AR Ligand Binding Domain (LBD) prefers to bind to the FxxLF motif. BUD31, a novel co-regulator with FxxLF motif, has been demonstrated to suppress wild-type and mutated AR-mediated prostate cancer growth.

Methods: To find out the interaction mechanisms of BUD31 with WT/T877A/W741L AR complex, molecular dynamics simulations were employed to study the complex BUD31 and WT/mutant ARs. The molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) results demonstrated that T877A and W741L point mutations can reduce the binding affinity between BUD31 and AR. The RMSF and dynamic cross-correlation analysis indicated that amino acid point mutations can affect the motions of loop residues in the AR structure.

Results: These results indicated that AR co-regulator binding site AF2 can serve as a target for drug discovery to solve the resistance problem.

Keywords: BUD31; Androgen receptor, AF2 binding site, interaction mechanism, molecular dynamics, co-regulator.

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