US2008227960A1PendingUtilityA1

Crystal structure of estrogen receptor-beta complex and uses thereof

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Assignee: GENETICS INST LLCPriority: Jul 11, 2001Filed: Apr 13, 2007Published: Sep 18, 2008
Est. expiryJul 11, 2021(expired)· nominal 20-yr term from priority
Inventors:William SomersZhang-Bao XuTatos AkopianChu-Lai HsiaoRayomand Unwalla
C07K 2299/00C07K 14/70567
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Claims

Abstract

This invention is directed to the crystal structure of Estrogen Receptor-β (ER-β) complexed with genistein, and to the use of this structure in rational drug design methods to identify agents that may interact with active sites of ER-β, which may be useful as novel chemotherapeutic agents.

Claims

exact text as granted — not AI-modified
1 . A crystallized Estrogen Receptor-β (ER-β) complexed with genistein. 
     
     
         2 . The crystallized ER-β complex of  claim 1 , characterized as having space group P2 1 2 1 2 1 . 
     
     
         3 - 15 . (canceled) 
     
     
         16 . A crystallized Estrogen Receptor-β (ER-β) complex, wherein the crystallized ER-β complex comprises an active site of ER-β. 
     
     
         17 . The crystallized ER-β complex of  claim 16 , wherein the crystal comprises the relative structural coordinates according to FIGS.  2 A- 2 XX for ER-β, ± a root mean square deviation from the backbone atoms of said amino acids of not more than 1.5 Å. 
     
     
         18 . The crystallized ER-β complex of  claim 16 , wherein the active site comprises the relative structural coordinates of amino acid residues MET343, LEU346, LEU349, GLU353, MET384, LEU387, MET388, ARG394, PHE404, ILE421, ILE424, GLY520,HIS523 and LEU524 according to FIGS.  2 A- 2 XX for monomer A of ER-β, ± a root mean square deviation from the backbone atoms of said amino acids of not more than 1.5 Å. 
     
     
         19 . The crystallized ER-β complex of  claim 18 , wherein the structural coordinates further comprise the relative structural coordinates of amino acid residues VAL328, MET342, SER345, THR347, LYS348, LEU349, ALA350, ASP351, LEU354, MET357, TRP383, GLU385, VAL386, MET389, GLY390, LEU391, MET392, LEU402, ILE403, ALA405, LEU408, VAL418, GLU419, GLY420, LEU422, GLU423, PHE425, LEU428, ALA516, SER517, LYS519, MET521, GLU522, LEU525, ASN526, MET527, LYS528, VAL533, VAL535, TYR536 and LEU538 according to FIGS.  2 A- 2 XX for monomer A of ER-β, ± a root mean square deviation from the backbone atoms of said amino acids of not more than 1.5 Å. 
     
     
         20 . The crystallized ER-β complex of  claim 16 ; wherein the active site comprises the relative structural coordinates of amino acid residues MET343, LEU346, LEU349, GLU353, MET384, LEU387, MET388, LEU391, ARG394, PHE404, ILE421, ILE424, GLY520,HIS523 and LEU524 according to FIGS.  2 A- 2 XX for monomer B of ER-β, ± a root mean square deviation from the backbone atoms of said amino acids of not more than 1.5 Å. 
     
     
         21 . The crystallized ER-β complex of  claim 20 , wherein the structural coordinates further comprise the relative structural coordinates of amino acid residues MET342, SER345, THR347, LYS348, ALA350, ASP351, MET357, TRP383, GLU385, VAL386, LEU387, MET389, GLY390, MET392, LEU402, ILE403, ALA405, LEU408, VAL418, GLU419, GLY420, LEU422, GLU423, PHE425, LEU428, ALA516, SER517, LYS519, MET521, GLU522, LEU525, ASN526, MET527, LYS528, VAL533, TYR536 and LEU538 according to FIGS.  2 A- 2 XX for monomer B of ER-β, ± a root mean square deviation from the backbone atoms of said amino acids of not more than 1.5 Å. 
     
     
         22 . The crystallized ER-β complex of  claim 2 , wherein the complex has the unit cell parameters of a=53.49Å, b=85.21 Å, and c=107.07 Å. 
     
     
         23 . The crystallized ER-β complex of  claim 16 , wherein ER-β comprises the amino acids 308-546 of ER-β as depicted in  FIG. 1 , or one or more conservative substitutions thereof. 
     
     
         24 . The crystallized ER-β complex of  claim 16 , wherein the complex consists of two ER-β molecules, each ER-β molecule bound to a genistein molecule. 
     
     
         25 . The crystallized ER-β complex of  claim 16 , wherein the crystal has a resolution of at least 1.8 Å resolution. 
     
     
         26 . The crystallized ER-β complex of  claim 16 , wherein the active site has the configuration of ER-β not bound to an agent. 
     
     
         27 . The crystallized ER-β complex of  claim 16 , wherein the active site has the configuration of ER-β bound to an agent. 
     
     
         28 . The crystallized ER-β complex of  claim 27 , wherein the agent comprises genistein. 
     
     
         29 . The crystallized ER-β complex of  claim 17 , wherein the active site has the configuration of ER-β not bound to an agent. 
     
     
         30 . The crystallized ER-β complex of  claim 17 , wherein the active site has the configuration of ER-β bound to an agent. 
     
     
         31 . The crystallized ER-β complex of  claim 30 , wherein the agent comprises genistein. 
     
     
         32 . The crystallized ER-β complex of  claim 18 , wherein the active site has the configuration of ER-β not bound to an agent. 
     
     
         33 . The crystallized ER-β complex of  claim 18 , wherein the active site has the configuration of ER-β bound to an agent. 
     
     
         34 . The crystallized ER-β complex of  claim 33 , wherein the agent comprises genistein. 
     
     
         35 . The crystallized ER-β complex of  claim 20 , wherein the active site has the configuration of ER-β not bound to an agent. 
     
     
         36 . The crystallized ER-β complex of  claim 20 , wherein the active site has the configuration of ER-β bound to an agent. 
     
     
         37 . The crystallized ER-β complex of  claim 36 , wherein the agent comprises genistein. 
     
     
         38 . The crystallized ER-β complex of  claim 17 , wherein the ± a root mean square deviation from the backbone atoms of said amino acids is not more than 1.0 Å. 
     
     
         39 . The crystallized ER-β complex of  claim 17 , wherein the ± a root mean square deviation from the backbone atoms of said amino acids is not more than 0.5 Å. 
     
     
         40 . The crystallized ER-β complex of  claim 18 , wherein the ± a root mean square deviation from the backbone atoms of said amino acids is not more than 1.0 Å. 
     
     
         41 . The crystallized ER-β complex of  claim 18 , wherein the ± a root mean square deviation from the backbone atoms of said amino acids is not more than 0.5 Å. 
     
     
         42 . The crystallized ER-β complex of  claim 20 , wherein the ± a root mean square deviation from the backbone atoms of said amino acids is not more than 1.0 Å. 
     
     
         43 . The crystallized ER-β complex of  claim 20 , wherein the ± a root mean square deviation from the backbone atoms of said amino acids is not more than 0.5 Å.

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