Crystal structure of a deacetylase and inhibitors thereof

Abstract

The present invention provides three-dimensional structural information from the hyperthermophilic bacterium Aquifex aeolicus which is a histone deacetylase-like protein (HDLP). HDLP shares 35.2% amino acid sequence identity with human histone deacetylase (HDAC1). The present invention further provides three-dimensional structural information of HDLP bound by inhibitor molecules. The three-dimensional structural information of the present invention is useful to design, isolate and screen deacetylase inhibitor compounds capable of inhibiting HDLP, HDAC family members and HDLP-related molecules. The invention also relates to nucleic acids encoding a mutant HDLP which facilitates the determination of the three-dimensional structure of HDLP in the presence of a zinc atom.

1 - 19 . (canceled)  
     
     
         20 . A method of evaluating the binding properties of the potential deacetylase inhibitor compound comprising the steps of: 
 (a) co-crystallizing said compound with HDLP;    (b) determining the three-dimensional structure of said HDLP-potential inhibitor complex co-crystal by molecular replacement using the three-dimensional structure of HDLP as defined by atomic coordinates according to  FIG. 16 ; and    (c) analyzing said three-dimensional structure of said HDLP bound to said potential inhibitor compound to evaluate the binding characteristics of said potential inhibitor compound.