Publication Date:
2000-07-07
Description:
Hypertension and pregnancy-related hypertension are major public health problems of largely unknown causes. We describe a mutation in the mineralocorticoid receptor (MR), S810L, that causes early-onset hypertension that is markedly exacerbated in pregnancy. This mutation results in constitutive MR activity and alters receptor specificity, with progesterone and other steroids lacking 21-hydroxyl groups, normally MR antagonists, becoming potent agonists. Structural and biochemical studies indicate that the mutation results in the gain of a van der Waals interaction between helix 5 and helix 3 that substitutes for interaction of the steroid 21-hydroxyl group with helix 3 in the wild-type receptor. This helix 5-helix 3 interaction is highly conserved among diverse nuclear hormone receptors, suggesting its general role in receptor activation.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Geller, D S -- Farhi, A -- Pinkerton, N -- Fradley, M -- Moritz, M -- Spitzer, A -- Meinke, G -- Tsai, F T -- Sigler, P B -- Lifton, R P -- New York, N.Y. -- Science. 2000 Jul 7;289(5476):119-23.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute, Department of Genetics, Yale University School of Medicine, Boyer Center for Molecular Medicine, Room 154, 295 Congress Avenue, New Haven, CT 06510, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/10884226" target="_blank"〉PubMed〈/a〉
Keywords:
Adolescent
;
Aldosterone/*metabolism
;
Amino Acid Sequence
;
Amino Acid Substitution
;
Base Sequence
;
Binding, Competitive
;
Dimerization
;
Female
;
Heterozygote
;
Humans
;
Hypertension/etiology/*genetics/metabolism
;
Male
;
Models, Molecular
;
Molecular Sequence Data
;
Pedigree
;
Point Mutation
;
Pregnancy
;
*Pregnancy Complications, Cardiovascular/etiology/metabolism
;
Progesterone/*metabolism
;
Protein Conformation
;
Protein Structure, Secondary
;
Receptors, Mineralocorticoid/chemistry/*genetics/*metabolism
;
Receptors, Steroid/chemistry/metabolism
;
Steroids/metabolism
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
,
Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
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