Linked Life Data

10419021

Source:http://linkedlifedata.com/resource/pubmed/id/10419021

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
1-6
pubmed:dateCreated
1999-8-2
pubmed:abstractText
Human estrogenic dehydrogenase (17beta-HSD1) catalyses the last step in the biosynthesis of the active estrogens that stimulate the proliferation of breast cancer cells. While the primary substrate for the enzyme is estrone, the enzyme has some activity for the non-estrogenic substrates. To better understand the structure function relationships of 17beta-HSD1 and to provide a better ground for the design of inhibitors, we have determined the crystal structures of 17beta-HSD1 in complex with different steroids. The structure of the complex of estradiol with the enzyme determined previously (Azzi et al., Nature Structural Biology 3, 665-668) showed that the narrow active site was highly complementary to the substrate. The substrate specificity is due to a combination of hydrogen bonding and hydrophobic interactions between the steroid and the enzyme binding pocket. We have now determined structures of 17beta-HSD1 in complex with dihydrotestosterone and 20alpha-OH-progesterone. In the case of the C19 androgen, several residues within the enzyme active site make some small adjustments to accommodate the increased bulk of the substrate. In addition, the C19 steroids bind in a slightly different position from estradiol with shifts in positions of up to 1.4 A. The altered binding position avoids unfavorable steric interactions between Leu 149 and the C19 methyl group (Han et al., unpublished). The known kinetic parameters for these substrates can be rationalized in light of the structures presented. These results give evidence for the structural basis of steroid recognition by 17beta-HSD1 and throw light on the design of new inhibitors for this pivotal steroid enzyme.
pubmed:commentsCorrections
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:issn
0960-0760
pubmed:author
pubmed:issnType
Print
pubmed:volume
69
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
425-9
pubmed:dateRevised
2006-11-15
pubmed:meshHeading
pubmed:articleTitle
3D-structure of human estrogenic 17beta-HSD1: binding with various steroids.
pubmed:affiliation
The Medical Research Council Group in Molecular Endocrinology, CHUL Research Center and Laval University, Sainte-Foy, QC, Canada. sxlin@crchul.ulaval.ca
pubmed:publicationType
Journal Article, Review, Research Support, Non-U.S. Gov't