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M Hage-van Noort,W C Puijk,H H Plasman,D Kuperus,W M Schaaper,N J Beekman,J A Grootegoed,R H Meloen
Central Veterinary Institute, Lelystad, The Netherlands.
Proc Natl Acad Sci U S A (P 0027-8424 E 0027-8424) H指数:699 1992 年 89 卷 9 期 3922-6 页
PMID:1315043 相似文献
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https://pubmed.ncbi.nlm.nih.gov/1315043/
Proc Natl Acad Sci U S A
. 1992 May 1;89(9):3922-6.
doi: 10.1073/pnas.89.9.3922.
Affiliations expand
PMID: 1315043
PMCID: PMC525603
Free PMC article
Proc Natl Acad Sci U S A 1993 Dec 15;90(24):12056
Follicle-stimulating hormone (follitropin, FSH) belongs to a group of closely related glycoprotein hormones that contain two noncovalently linked dissimilar subunits designated alpha and beta. By using synthetic peptides, several receptor interaction sites in these hormones have been identified; however, the peptides have a reduced potency (lowest effective concentration of 10(-4) to 10(-5) M) relative to the hormone itself (10(-8) to 10(-11) M). This suggests that the peptides represent only a portion of a larger recognition site in the intact hormone that comprises parts of both the beta and the alpha chains. To develop peptides that exhibit FSH-antagonistic activity at low concentrations, we have constructed a three-dimensional model for FSH, which is based on an alignment of both the beta and the alpha chains of glycoprotein hormones with thioredoxin, for which x-ray diffraction data are available. This model resulted in the prediction of a conformational receptor-binding site in FSH, in which (parts of) three earlier proposed binding regions on the FSH molecule [namely, the regions FSH alpha-(34-37), with the amino acid sequence SRAY; FSH beta-(40-43), with the amino acid sequence TRDL; and FSH beta-(87-94), the "determinant loop" with the amino acid sequence CDSDSTDC] are located within 10 A of one another. On the basis of this model, peptides have been synthesized in which two of these binding regions are linked by a synthetic amino acid whose length was derived from the model, Ac-TDSDS-NH-(CH2)5-CO-SRAY-NH2 and Ac-SRAY-NH-(CH2)4-CO-TRDL-NH2. Both peptides inhibited FSH-induced cAMP production in Sertoli cells at 1000-fold lower concentrations (10(-7) M) than the peptides Ac-TRDL-NH2, Ac-SRAY-NH2, or Ac-TDSDS-NH2. In another peptide, Ac-TDSDS-NH-(CH2)5-CO-SRAY-NH-(CH2)4-CO-TRDL-NH2, all three binding regions have been linked. This peptide appeared to be a strong agonist of FSH action, as measured by the ability to stimulate cAMP production, at concentrations as low as 10(-7) M. The observation that a synthetic peptide, in which (parts of) three earlier described receptor interaction sites are combined according to the three-dimensional model, can mimic the action of FSH, at 10(-7) M, shows that this model is useful to predict a conformational receptor-binding site in FSH and that combination of only a few amino acid residues from the alpha and beta chains of FSH in a small synthetic peptide is sufficient to transduce a signal upon binding to the receptor.
Pept Res. 1995 Sep-Oct;8(5):272-7.PMID: 8589549
Mol Cell Endocrinol. 1996 Dec 20;125(1-2):45-54. doi: 10.1016/s0303-7207(96)03947-0.PMID: 9027342 Review.
Mol Cell Endocrinol. 1995 Apr 28;110(1-2):35-41. doi: 10.1016/0303-7207(95)91392-t.PMID: 7672451
Mol Cell Endocrinol. 1993 May;93(1):39-46. doi: 10.1016/0303-7207(93)90137-9.PMID: 8319832
Structural biology of human follitropin and its receptor.
Arch Med Res. 2001 Nov-Dec;32(6):510-9. doi: 10.1016/s0188-4409(01)00333-2.PMID: 11750726 Review.
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Show all 45 references
Research Support, Non-U.S. Gov't
MeSH terms 本文的主题词
Amino Acid Sequence
Animals
Binding Sites
Chorionic Gonadotropin / chemistry
Cyclic AMP / biosynthesis
Drug Design
Follicle Stimulating Hormone* / analogs & derivatives
Follicle Stimulating Hormone* / antagonists & inhibitors
Follicle Stimulating Hormone* / metabolism
Glutaredoxins
In Vitro Techniques
Male
Molecular Sequence Data
Oxidoreductases*
Protein Conformation
Proteins / chemistry
Rats
Receptors, FSH / chemistry*
Receptors, FSH / metabolism
Sertoli Cells / metabolism
Structure-Activity Relationship
Thioredoxins / chemistry
Substances 化学物质
Chorionic Gonadotropin
Glutaredoxins
Proteins
Receptors, FSH
Thioredoxins
Follicle Stimulating Hormone
Cyclic AMP
Oxidoreductases
Related information 相关信息
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