Crystal Structure of Murine 11β-Hydroxysteroid Dehydrogenase 1:  An Important Therapeutic Target for Diabetes

Abstract

11Beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) catalyzes the conversion of 11-dehydrocorticosterone to its active form corticosterone in rodents (or cortisone to cortisol in humans). The reductive reaction of the 11-keto to 11-hydroxyl is the pivotal switch in the activation of glucocorticoids. An excess of active glucocorticoids has been shown to play a key role in metabolic disorders such as diabetes and obesity. Therefore, 11beta-HSD1 represents an important therapeutic target for the treatment of these diseases. To facilitate the iterative design of inhibitors, we have crystallized and determined the three-dimensional structures of a binary complex of murine 11beta-HSD1 with NADP(H) to a resolution of 2.3 A and of a ternary complex with corticosterone and NADP(H) to a resolution of 3.0 A by X-ray crystallography. The enzyme forms a homodimer in the crystal and has a fold similar to those of other members of the family of short chain steroid dehydrogenases/reductases (SDRs). The structure shows a novel folding feature at the C-terminus of the enzyme. The C-terminal helix insertions provide additional dimer contacts, exert an influence on the conformations of the substrate binding loops, and present hydrophobic regions for potential membrane attachment. The structure also reveals how 11beta-HSD1 achieves its selectivity for its substrate.

Alterations of Cortisol Metabolism in Human Disorders

“…The corresponding human gene for this isozyme, HSD11B1 , is located on chromosome 1 and contains 6 exons with a total length of over 9 kb. Crystal structures of 11-HSD1 are available [5] and have been extensively used for the identification of specific inhibitors of the enzyme [6, 7]. …”

Development of 11β -HSD1 Inhibitors for the Treatment of Type 2 Diabetes

“…In all cases, the structures were resolved using truncated enzymes lacking the N-terminal membrane attachment domain expressed in E. coli [24][25][26]. The enzyme is a homodimer of two subunits with the C-terminus of one subunit interacting with the active site of the other [24][25][26].…”

“…In all cases, the structures were resolved using truncated enzymes lacking the N-terminal membrane attachment domain expressed in E. coli [24][25][26]. The enzyme is a homodimer of two subunits with the C-terminus of one subunit interacting with the active site of the other [24][25][26]. The key residues in substrate binding include the signature motif YSASK at the catalytic center, with Y183 (human) being the key residue [24][25][26].…”

“…The enzyme is a homodimer of two subunits with the C-terminus of one subunit interacting with the active site of the other [24][25][26]. The key residues in substrate binding include the signature motif YSASK at the catalytic center, with Y183 (human) being the key residue [24][25][26]. The serine residues determine the rate of catalysis but are not involved in substrate binding [27].…”

“…One interesting observation is the variation of compound potency across species (see below and Table 1). There are significant differences between the binding pockets of human and mouse enzymes [25,26], which provides a structural basis for the cross-species potency shifts. Since most pharmacodynamic (PD) and diabetes models are rodents, acceptable rodent (especially mouse) potency makes it convenient to evaluate the PD effect and efficacy of a given compound.…”