2pnu
From Proteopedia
(New page: 200px<br /> <applet load="2pnu" size="450" color="white" frame="true" align="right" spinBox="true" caption="2pnu, resolution 1.650Å" /> '''Crystal structure ...) |
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caption="2pnu, resolution 1.650Å" /> | caption="2pnu, resolution 1.650Å" /> | ||
'''Crystal structure of human androgen receptor ligand-binding domain in complex with EM-5744'''<br /> | '''Crystal structure of human androgen receptor ligand-binding domain in complex with EM-5744'''<br /> | ||
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==Overview== | ==Overview== | ||
The androgen receptor (AR) mediates the action of androgens in normal, conditions as well as in pathological states. Antiandrogens are thus, commonly used to treat androgen-dependent disorders. The currently used, drugs unfortunately possess very weak affinity for the human AR (hAR), thus indicating the need to develop new high-affinity steroidal, antiandrogens. Our compounds are specially designed to impede, repositioning of the mobile carboxy-terminal helix 12, which blocks the, ligand-dependant transactivation function (AF-2) located in the AR, ligand-binding domain (ARLBD). Using crystal structures of the hARLBD, we, first found that H12 could be directly reached from the ligand-binding, pocket (LBP) by a chain positioned on the C18 atom of an androgen steroid, nucleus. A set of DHT-derived molecules bearing various C18 chains were, thus synthesized and tested for their capacity to bind hAR and act as, antagonists. Although most of those having very high affinity for hAR were, agonists, several very potent antagonists were obtained, confirming the, structural importance of the C18 chain. To understand the role of the C18, chain in their agonistic/antagonistic properties, the structure of the, hARLBD complexed with one of these agonists, EM5744, was determined at a, 1.65 A resolution. We have identified new interactions involving Gln738, Met742 and His874 that explain both the high-affinity of this compound and, the inability of its bulky chain to prevent the repositioning of H12., These structural informations will be helpful to refine the structure of, the chains placed on the C18 atom in order to obtain efficient, H12-directed steroidal antiandrogens. | The androgen receptor (AR) mediates the action of androgens in normal, conditions as well as in pathological states. Antiandrogens are thus, commonly used to treat androgen-dependent disorders. The currently used, drugs unfortunately possess very weak affinity for the human AR (hAR), thus indicating the need to develop new high-affinity steroidal, antiandrogens. Our compounds are specially designed to impede, repositioning of the mobile carboxy-terminal helix 12, which blocks the, ligand-dependant transactivation function (AF-2) located in the AR, ligand-binding domain (ARLBD). Using crystal structures of the hARLBD, we, first found that H12 could be directly reached from the ligand-binding, pocket (LBP) by a chain positioned on the C18 atom of an androgen steroid, nucleus. A set of DHT-derived molecules bearing various C18 chains were, thus synthesized and tested for their capacity to bind hAR and act as, antagonists. Although most of those having very high affinity for hAR were, agonists, several very potent antagonists were obtained, confirming the, structural importance of the C18 chain. To understand the role of the C18, chain in their agonistic/antagonistic properties, the structure of the, hARLBD complexed with one of these agonists, EM5744, was determined at a, 1.65 A resolution. We have identified new interactions involving Gln738, Met742 and His874 that explain both the high-affinity of this compound and, the inability of its bulky chain to prevent the repositioning of H12., These structural informations will be helpful to refine the structure of, the chains placed on the C18 atom in order to obtain efficient, H12-directed steroidal antiandrogens. | ||
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| - | ==Disease== | ||
| - | Known diseases associated with this structure: Androgen insensitivity OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=313700 313700]], Breast cancer, male, with Reifenstein syndrome OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=313700 313700]], Hypospadias, perineal OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=313700 313700]], Prostate cancer OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=313700 313700]], Prostate cancer, susceptibility to OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=313700 313700]], Spinal and bulbar muscular atrophy of Kennedy OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=313700 313700]] | ||
==About this Structure== | ==About this Structure== | ||
| - | 2PNU is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with SO4, ENM, DTT and MES as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http:// | + | 2PNU is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=SO4:'>SO4</scene>, <scene name='pdbligand=ENM:'>ENM</scene>, <scene name='pdbligand=DTT:'>DTT</scene> and <scene name='pdbligand=MES:'>MES</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2PNU OCA]. |
==Reference== | ==Reference== | ||
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[[Category: ligand binding domain]] | [[Category: ligand binding domain]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Jan 23 12:33:13 2008'' |
Revision as of 10:33, 23 January 2008
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Crystal structure of human androgen receptor ligand-binding domain in complex with EM-5744
Overview
The androgen receptor (AR) mediates the action of androgens in normal, conditions as well as in pathological states. Antiandrogens are thus, commonly used to treat androgen-dependent disorders. The currently used, drugs unfortunately possess very weak affinity for the human AR (hAR), thus indicating the need to develop new high-affinity steroidal, antiandrogens. Our compounds are specially designed to impede, repositioning of the mobile carboxy-terminal helix 12, which blocks the, ligand-dependant transactivation function (AF-2) located in the AR, ligand-binding domain (ARLBD). Using crystal structures of the hARLBD, we, first found that H12 could be directly reached from the ligand-binding, pocket (LBP) by a chain positioned on the C18 atom of an androgen steroid, nucleus. A set of DHT-derived molecules bearing various C18 chains were, thus synthesized and tested for their capacity to bind hAR and act as, antagonists. Although most of those having very high affinity for hAR were, agonists, several very potent antagonists were obtained, confirming the, structural importance of the C18 chain. To understand the role of the C18, chain in their agonistic/antagonistic properties, the structure of the, hARLBD complexed with one of these agonists, EM5744, was determined at a, 1.65 A resolution. We have identified new interactions involving Gln738, Met742 and His874 that explain both the high-affinity of this compound and, the inability of its bulky chain to prevent the repositioning of H12., These structural informations will be helpful to refine the structure of, the chains placed on the C18 atom in order to obtain efficient, H12-directed steroidal antiandrogens.
About this Structure
2PNU is a Single protein structure of sequence from Homo sapiens with , , and as ligands. Full crystallographic information is available from OCA.
Reference
Structural characterization of the human androgen receptor ligand-binding domain complexed with EM5744, a rationally-designed steroidal ligand bearing a bulky chain directed toward helix 12., Cantin L, Faucher F, Couture JF, Pereira de Jesus-Tran K, Legrand P, Ciobanu LC, Frechette Y, Labrecque R, Singh SM, Labrie F, Breton R, J Biol Chem. 2007 Aug 21;. PMID:17711855
Page seeded by OCA on Wed Jan 23 12:33:13 2008
Categories: Homo sapiens | Single protein | Breton, R. | Cantin, L. | Ciobanu, C.L. | Couture, J.F. | Faucher, F. | Jesus-Tran, K.Pereira.de. | Labrie, F. | Legrand, P. | Singh, S.M. | DTT | ENM | MES | SO4 | Androgen | Androgen receptor | Dht | Har | Hormone/gene regulation complex | Lbd | Ligand binding domain
