Corticosteroid-binding globulin: structure-function implications from species differences.

Article Details

Citation

Gardill BR, Vogl MR, Lin HY, Hammond GL, Muller YA

Corticosteroid-binding globulin: structure-function implications from species differences.

PLoS One. 2012;7(12):e52759. doi: 10.1371/journal.pone.0052759. Epub 2012 Dec 26.

PubMed ID
23300763 [ View in PubMed
]
Abstract

Corticosteroid-binding globulin (CBG) transports glucocorticoids and progesterone in the blood and thereby modulates the tissue availability of these hormones. As a member of the serine protease inhibitor (SERPIN) family, CBG displays a reactive center loop (RCL) that is targeted by proteinases. Cleavage of the RCL is thought to trigger a SERPIN-typical stressed-to-relaxed (S-to-R) transition that leads to marked structural rearrangements and a reduced steroid-binding affinity. To characterize structure-function relationships in CBG we studied various conformational states of E. coli-produced rat and human CBG. In the 2.5 A crystal structure of human CBG in complex with progesterone, the RCL is cleaved at a novel site that differs from the known human neutrophil elastase recognition site. Although the cleaved RCL segment is five residues longer than anticipated, it becomes an integral part of beta-sheet A as a result of the S-to-R transition. The atomic interactions observed between progesterone and CBG explain the lower affinity of progesterone in comparison to corticosteroids. Surprisingly, CD measurements in combination with thermal unfolding experiments show that rat CBG fails to undergo an S-to-R transition upon proteolytic cleavage of the RCL hinting that the S-to-R transition observed in human CBG is not a prerequisite for CBG function in rat. This observation cautions against drawing general conclusions about molecular mechanisms by comparing and merging structural data from different species.

DrugBank Data that Cites this Article

Drugs
Drug Carriers
DrugCarrierKindOrganismPharmacological ActionActions
Betamethasone phosphateCorticosteroid-binding globulinProteinHumans
Unknown
Binder
Details
BudesonideCorticosteroid-binding globulinProteinHumans
Unknown
Binder
Details
Clobetasol propionateCorticosteroid-binding globulinProteinHumans
Unknown
Binder
Details
Cortisone acetateCorticosteroid-binding globulinProteinHumans
Unknown
Binder
Details
FlunisolideCorticosteroid-binding globulinProteinHumans
No
Binder
Details
FluorometholoneCorticosteroid-binding globulinProteinHumans
Unknown
Not AvailableDetails
FluticasoneCorticosteroid-binding globulinProteinHumans
Unknown
Not AvailableDetails
Fluticasone furoateCorticosteroid-binding globulinProteinHumans
Unknown
Not AvailableDetails
Fluticasone propionateCorticosteroid-binding globulinProteinHumans
Unknown
Not AvailableDetails
HydrocortisoneSex hormone-binding globulinProteinHumans
Unknown
Binder
Details
MedrysoneCorticosteroid-binding globulinProteinHumans
Unknown
Binder
Details
Prednisolone phosphateCorticosteroid-binding globulinProteinHumans
Unknown
Binder
Details
PrednisoneCorticosteroid-binding globulinProteinHumans
Unknown
Binder
Details
UlobetasolCorticosteroid-binding globulinProteinHumans
Unknown
Binder
Details