2h44

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(New page: 200px<br /> <applet load="2h44" size="450" color="white" frame="true" align="right" spinBox="true" caption="2h44, resolution 1.8&Aring;" /> '''Crystal structure of...)
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<applet load="2h44" size="450" color="white" frame="true" align="right" spinBox="true"
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'''Crystal structure of PDE5A1 in complex with icarisid II'''<br />
'''Crystal structure of PDE5A1 in complex with icarisid II'''<br />
==Overview==
==Overview==
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Phosphodiesterase-5 (PDE5) is the target for sildenafil, vardenafil, and, tadalafil, which are drugs for treatment of erectile dysfunction and, pulmonary hypertension. We report here the crystal structures of a fully, active catalytic domain of unliganded PDE5A1 and its complexes with, sildenafil or icarisid II. These structures together with the, PDE5A1-isobutyl-1-methylxanthine complex show that the H-loop (residues, 660-683) at the active site of PDE5A1 has four different conformations and, migrates 7-35A upon inhibitor binding. In addition, the conformation of, sildenafil reported herein differs significantly from those in the, previous structures of chimerically hybridized or almost inactive PDE5., Mutagenesis and kinetic analyses confirm that the H-loop is particularly, important for substrate recognition and that invariant Gly(659), which, immediately precedes the H-loop, is critical for optimal substrate, affinity and catalytic activity.
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Phosphodiesterase-5 (PDE5) is the target for sildenafil, vardenafil, and tadalafil, which are drugs for treatment of erectile dysfunction and pulmonary hypertension. We report here the crystal structures of a fully active catalytic domain of unliganded PDE5A1 and its complexes with sildenafil or icarisid II. These structures together with the PDE5A1-isobutyl-1-methylxanthine complex show that the H-loop (residues 660-683) at the active site of PDE5A1 has four different conformations and migrates 7-35A upon inhibitor binding. In addition, the conformation of sildenafil reported herein differs significantly from those in the previous structures of chimerically hybridized or almost inactive PDE5. Mutagenesis and kinetic analyses confirm that the H-loop is particularly important for substrate recognition and that invariant Gly(659), which immediately precedes the H-loop, is critical for optimal substrate affinity and catalytic activity.
==About this Structure==
==About this Structure==
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2H44 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 ZN, MG and 7CA as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/3',5'-cyclic-GMP_phosphodiesterase 3',5'-cyclic-GMP phosphodiesterase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.1.4.35 3.1.4.35] Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=2H44 OCA].
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2H44 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=ZN:'>ZN</scene>, <scene name='pdbligand=MG:'>MG</scene> and <scene name='pdbligand=7CA:'>7CA</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/3',5'-cyclic-GMP_phosphodiesterase 3',5'-cyclic-GMP phosphodiesterase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.1.4.35 3.1.4.35] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2H44 OCA].
==Reference==
==Reference==
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[[Category: pde5a inhibitor]]
[[Category: pde5a inhibitor]]
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''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 22:26:01 2007''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 17:37:59 2008''

Revision as of 15:38, 21 February 2008

Image:2h44.gif

2h44, resolution 1.8Å

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Crystal structure of PDE5A1 in complex with icarisid II

Overview

Phosphodiesterase-5 (PDE5) is the target for sildenafil, vardenafil, and tadalafil, which are drugs for treatment of erectile dysfunction and pulmonary hypertension. We report here the crystal structures of a fully active catalytic domain of unliganded PDE5A1 and its complexes with sildenafil or icarisid II. These structures together with the PDE5A1-isobutyl-1-methylxanthine complex show that the H-loop (residues 660-683) at the active site of PDE5A1 has four different conformations and migrates 7-35A upon inhibitor binding. In addition, the conformation of sildenafil reported herein differs significantly from those in the previous structures of chimerically hybridized or almost inactive PDE5. Mutagenesis and kinetic analyses confirm that the H-loop is particularly important for substrate recognition and that invariant Gly(659), which immediately precedes the H-loop, is critical for optimal substrate affinity and catalytic activity.

About this Structure

2H44 is a Single protein structure of sequence from Homo sapiens with , and as ligands. Active as 3',5'-cyclic-GMP phosphodiesterase, with EC number 3.1.4.35 Full crystallographic information is available from OCA.

Reference

Multiple conformations of phosphodiesterase-5: implications for enzyme function and drug development., Wang H, Liu Y, Huai Q, Cai J, Zoraghi R, Francis SH, Corbin JD, Robinson H, Xin Z, Lin G, Ke H, J Biol Chem. 2006 Jul 28;281(30):21469-79. Epub 2006 May 30. PMID:16735511

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