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J. Biol. Chem., Vol. 275, Issue 34, 26164-26171, August 25, 2000
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From the The crystal structures of the human androgen
receptor (hAR) and human progesterone receptor ligand-binding domains
in complex with the same ligand metribolone (R1881) have been
determined. Both three-dimensional structures show the typical nuclear
receptor fold. The change of two residues in the ligand-binding pocket between the human progesterone receptor and hAR is most likely the
source for the specificity of R1881 to the hAR. The structural implications of the 14 known mutations in the ligand-binding pocket of
the hAR ligand-binding domains associated with either prostate cancer
or the partial or complete androgen receptor insensitivity syndrome
were analyzed. The effects of most of these mutants could be explained
on the basis of the crystal structure.
The atomic coordinates and structure factors (code 1e3g and 1e3k)
have been deposited in the Protein Data Bank, Research Collaboratory
for Structural Bioinformatics, Rutgers University, New Brunswick, NJ
(http://www.rcsb.org/).
Structural Evidence for Ligand Specificity in the Binding Domain
of the Human Androgen Receptor
IMPLICATIONS FOR PATHOGENIC GENE MUTATIONS*
,,¶,,
Instituto de Tecnologia Química e
Biológica, Universidade Nova de Lisboa, Apartado 127, 2780 Oeiras, Portugal, § Schering AG Research Laboratories,
13342 Berlin, Germany, and the ¶ Instituto de Biologia
Experimental e Tecnológica, Apartado 12, 2780 Oeiras, Portugal
*
This work was supported in part by Agência de
Inovação S.A. (Lisboa, Portugal) within the EUREKA project
1948 SASTEREC and the European Synchrotron Radiation Facility
(Grenoble, France).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed. Tel.:
351-21-446-9657; Fax: 351-21-443-3644; E-mail:
carrondo@itqb.unl.pt.
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