Glycoprotein hormones tied but not tethered like other cysteine-knot cytokines.
A new crystal structure of the pituitary glycoprotein human follicle-stimulating hormone (hFSH) in complex with a fragment of the human FSH receptor (hFSHR(1-250)) ectodomain has been determined. The hFSH receptor is a Class A rhodopsin-like G-protein-coupled receptor (GPCR). The structure serves as a template for the modeling of the related luteinizing hormone (LH) and thyroid-stimulating hormone (TSH) receptors and explains why these hormones do not cross-react with the FSH receptor. Unexpectedly, the FSH receptor ectodomain in complex with FSH is a dimer but, unlike other cysteine-knot cytokines, FSH does not participate in a receptor-receptor tether. A host of biochemical data can now be placed in the context of the new structure, and will provide new insights that could lead to the development of small-molecule contraceptives and more-active or bifunctional versions of hormones for FSH receptor and other related receptors.
Krystek
Stanley R
SR
Bristol-Myers Squibb Pharmaceutical Research Institute, Department of Computer-Assisted Drug Design, PO Box 5400, Princeton, NJ 08543-5400, USA.
Dias
James A
JA
D000595:Amino Acid Sequence; D003460:Crystallization; D005640:Follicle Stimulating Hormone / Q000737:chemistry*; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry; D017434:Protein Structure, Tertiary; D021122:Protein Subunits; D011962:Receptors, FSH / Q000737:chemistry*
D010446:Peptide Fragments; D021122:Protein Subunits; D011962:Receptors, FSH; D005640:Follicle Stimulating Hormone