2zcl
From Proteopedia
(New page: 200px<br /><applet load="2zcl" size="350" color="white" frame="true" align="right" spinBox="true" caption="2zcl, resolution 3.25Å" /> '''Crystal structure of...) |
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==Overview== | ==Overview== | ||
| - | Human prostate-specific antigen (PSA or KLK3) is an important marker for | + | Human prostate-specific antigen (PSA or KLK3) is an important marker for the diagnosis and management of prostate cancer. This is an androgen-regulated glycoprotein of the kallikrein-related protease family secreted by prostatic epithelial cells. Its physiological function is to cleave semenogelins in the seminal coagulum and its enzymatic activity is strongly modulated by zinc ions. Here we present the first crystal structure of human PSA in complex with monoclonal antibody (mAb) 8G8F5 that enhances its enzymatic activity. The mAb recognizes an epitope composed of five discontinuous segments including residues from the kallikrein loop and stabilizes PSA in an "open and active conformation" that accelerates catalysis. We also present the crystal structure of PSA in complex with both the mAb 8G8F5 and a fluorogenic substrate Mu-KGISSQY-AFC, derived from semenogelin I. By exploiting the inhibition of PSA by zinc ions, we were able to obtain a substrate acyl intermediate covalently linked to the catalytic serine, at pH 7.3 but not at pH 5.5. Moreover, the inhibition of PSA activity by zinc was found to be modulated by pH variations but not by the antibody binding. The correlation of the different data with the physiological conditions under which PSA can cleave semenogelins is discussed. |
==About this Structure== | ==About this Structure== | ||
| - | 2ZCL is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [http://en.wikipedia.org/wiki/Mus_musculus Mus musculus] with <scene name='pdbligand=NAG:'>NAG</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Semenogelase Semenogelase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.21.77 3.4.21.77] Known structural/functional Site: <scene name='pdbsite=AC1:Nag Binding Site For Residue P 401'>AC1</scene>. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2ZCL OCA]. | + | 2ZCL is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [http://en.wikipedia.org/wiki/Mus_musculus Mus musculus] with <scene name='pdbligand=NAG:'>NAG</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Semenogelase Semenogelase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.21.77 3.4.21.77] Known structural/functional Site: <scene name='pdbsite=AC1:Nag+Binding+Site+For+Residue+P+401'>AC1</scene>. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2ZCL OCA]. |
==Reference== | ==Reference== | ||
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[[Category: zymogen]] | [[Category: zymogen]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 19:01:25 2008'' |
Revision as of 17:01, 21 February 2008
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Crystal structure of human prostate specific antigen complexed with an activating antibody
Overview
Human prostate-specific antigen (PSA or KLK3) is an important marker for the diagnosis and management of prostate cancer. This is an androgen-regulated glycoprotein of the kallikrein-related protease family secreted by prostatic epithelial cells. Its physiological function is to cleave semenogelins in the seminal coagulum and its enzymatic activity is strongly modulated by zinc ions. Here we present the first crystal structure of human PSA in complex with monoclonal antibody (mAb) 8G8F5 that enhances its enzymatic activity. The mAb recognizes an epitope composed of five discontinuous segments including residues from the kallikrein loop and stabilizes PSA in an "open and active conformation" that accelerates catalysis. We also present the crystal structure of PSA in complex with both the mAb 8G8F5 and a fluorogenic substrate Mu-KGISSQY-AFC, derived from semenogelin I. By exploiting the inhibition of PSA by zinc ions, we were able to obtain a substrate acyl intermediate covalently linked to the catalytic serine, at pH 7.3 but not at pH 5.5. Moreover, the inhibition of PSA activity by zinc was found to be modulated by pH variations but not by the antibody binding. The correlation of the different data with the physiological conditions under which PSA can cleave semenogelins is discussed.
About this Structure
2ZCL is a Protein complex structure of sequences from Homo sapiens and Mus musculus with as ligand. Active as Semenogelase, with EC number 3.4.21.77 Known structural/functional Site: . Full crystallographic information is available from OCA.
Reference
Crystal Structure of a Ternary Complex between Human Prostate-specific Antigen, Its Substrate Acyl Intermediate and an Activating Antibody., Menez R, Michel S, Muller BH, Bossus M, Ducancel F, Jolivet-Reynaud C, Stura EA, J Mol Biol. 2007 Nov 22;. PMID:18187150
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Categories: Homo sapiens | Mus musculus | Protein complex | Semenogelase | Jolivet-Reynaud, C. | Menez, R. | Stura, E. | NAG | Antibodies | Glycoprotein | Human psa | Hydrolase | Immune system | Kallikrein related peptidases | Polymorphism | Prostate cancer | Protease | Secreted | Serine protease | Zymogen
