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結構生物學

結構生物學. 生技所 吳貫忠 D93360003. Crystallographic comparison of the estrogen and progesterone receptor ’ s ligand binding domains. Tanenbaum D. M., Wang Y., Williams S. P., and Sigler P. B. 1998. Proc. Natl. Acad. Sci. USA 95:5998-6003.

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結構生物學

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  1. 結構生物學 生技所 吳貫忠 D93360003

  2. Crystallographic comparison of the estrogen and progesterone receptor’s ligand binding domains Tanenbaum D. M., Wang Y., Williams S. P., and Sigler P. B. 1998. Proc. Natl. Acad. Sci. USA 95:5998-6003. Department of Molecular Biophysics and Biochemistry and the Howard Hughes Medical Institute, Yale University, 260 Whitney Avenue, JWG 423,New Haven, CT 06511 PDB ID : ERαLBD 1A52 PGRLBD 1A28

  3. Hormone receptor’s ligand binding domain • Members of this family are modular in structure with domains A-F, including discrete DNA binding domain and ligand binding domain. • The receptors are targeted to their respective promoters through specific interaction with cognate hormone response elements, and regulate transcription in a ligand-dependent manner with the aid of various coactivators and corepressors.

  4. Estrogen receptor’s ligand binding domain • Overall Architecture • Dimer Interface • Hormone Specificity • Coactivator Binding

  5. Overall Architecture c4 zinc finger (DBD) 01mtmtlhtkasgmallhqiqgneleplnrpqlkiplerplgevyldsskpavynypegaayefnaaaaanaqvygqtglpygpgseaaafgsnglggfpplnsvspsplmllhpppqlspflqphgqqvpyylenepsgytvreagppafyrpnsdnrrqggrerlastndkgsmamesaketrycavcndyasgyhygvwscegckaffkrsiqghndymcpatnqctidknrrkscqacrlrkcyevgmmkggirkdrrggrmlkhkrqrddgegrgevgsagdmraanlwpsplmikrskknslalsltadqmvsalldaeppilyseydptrpfseasmmglltnladrelvhminwakrvpgfvdltlhdqvhllecawleilmiglvwrsmehpgkllfapnllldrnqgkcvegmveifdmllatssrfrmmnlqgeefvclksiillnsgvytflsstlksleekdhihrvldkitdtlihlmakagltlqqqhqrlaqlllilshirhmsnkgmehlysmkcknvvplydlllemldahrlhaptsrggasveetdqshlatagstsshslqkyyitgeaegfpatv 596 Ligand binding domain

  6. PR ER AR PR ER AR PR ER AR

  7. N N estrodil estrodiol C C

  8. C C N N Progesterone

  9. Dimer Interface • Gel filtration experiments on a slightly longer fragment of hERαLBD show that the estradiol-bound hERαLBD is a dimer in solution, whereas the progesterone-bound hPGRLBD used for the crystal structure elutes as a monomer.

  10. H7 ER ER C H10 H9 N PGR H7 H10 C N H9

  11. Helix 10 Helix 7 Helix 9 Ala 430 Arg 434 Ile 451 Asn 455 Tyr 459 Thr 460 Asp 480 Thr 483 Asp 484 Ile 487 Leu 497 Gln 498 His 501 Glu 506 Leu 508 Leu 509 Ile 510 Leu 511 Ser 512 His 513 Arg 515 His 516 Asn 519 Glu 523

  12. Hormone Specificity

  13. Coactivator Binding • Coactivator are necessary for the hormone -bound ER/PGR to stimulate transcription.

  14. Resurrecting the Ancestral steroid receptor: Ancient Origin of Estrogen Signaling • Vertebrate genomes contains six evolutionarily related nuclear receptors for steroid hormone. (two for estrogen and one each for androgen, progesterone, glucocorticoid, and mineralo-corticoid) • In Aplysia, the ER-LBD binding affinity lower than the human ER-LBD.

  15. The expected biological insight I will gain through the analysis • Which difference between human ER-LBD and Aplysia ER-LBD. • Have a functional change of Aplysia ER?

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