1tbf: Difference between revisions

Revision as of 16:11, 21 February 2008

Catalytic Domain Of Human Phosphodiesterase 5A in Complex with Sildenafil

OverviewOverview

Phosphodiesterases (PDEs) comprise a family of enzymes that modulate the immune response, inflammation, and memory, among many other functions. There are three types of PDEs: cAMP-specific, cGMP-specific, and dual-specific. Here we describe the mechanism of nucleotide selectivity on the basis of high-resolution co-crystal structures of the cAMP-specific PDE4B and PDE4D with AMP, the cGMP-specific PDE5A with GMP, and the apo-structure of the dual-specific PDE1B. These structures show that an invariant glutamine functions as the key specificity determinant by a "glutamine switch" mechanism for recognizing the purine moiety in cAMP or cGMP. The surrounding residues anchor the glutamine residue in different orientations for cAMP and for cGMP. The PDE1B structure shows that in dual-specific PDEs a key histidine residue may enable the invariant glutamine to toggle between cAMP and cGMP. The structural understanding of nucleotide binding enables the design of new PDE inhibitors that may treat diseases in which cyclic nucleotides play a critical role.

About this StructureAbout this Structure

1TBF is a Single protein structure of sequence from Homo sapiens with , , and as ligands. Active as 3',5'-cyclic-nucleotide phosphodiesterase, with EC number 3.1.4.17 Full crystallographic information is available from OCA.

ReferenceReference

A glutamine switch mechanism for nucleotide selectivity by phosphodiesterases., Zhang KY, Card GL, Suzuki Y, Artis DR, Fong D, Gillette S, Hsieh D, Neiman J, West BL, Zhang C, Milburn MV, Kim SH, Schlessinger J, Bollag G, Mol Cell. 2004 Jul 23;15(2):279-86. PMID:15260978

Page seeded by OCA on Thu Feb 21 15:11:48 2008

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OCA

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-[[Image:1tbf.gif|left|200px]]<br />
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 caption="1tbf, resolution 1.30&Aring;" />
 '''Catalytic Domain Of Human Phosphodiesterase 5A in Complex with Sildenafil'''<br />
 ==Overview==
-Phosphodiesterases (PDEs) comprise a family of enzymes that modulate the, immune response, inflammation, and memory, among many other functions., There are three types of PDEs: cAMP-specific, cGMP-specific, and, dual-specific. Here we describe the mechanism of nucleotide selectivity on, the basis of high-resolution co-crystal structures of the cAMP-specific, PDE4B and PDE4D with AMP, the cGMP-specific PDE5A with GMP, and the, apo-structure of the dual-specific PDE1B. These structures show that an, invariant glutamine functions as the key specificity determinant by a, "glutamine switch" mechanism for recognizing the purine moiety in cAMP or, cGMP. The surrounding residues anchor the glutamine residue in different, orientations for cAMP and for cGMP. The PDE1B structure shows that in, dual-specific PDEs a key histidine residue may enable the invariant, glutamine to toggle between cAMP and cGMP. The structural understanding of, nucleotide binding enables the design of new PDE inhibitors that may treat, diseases in which cyclic nucleotides play a critical role.
+Phosphodiesterases (PDEs) comprise a family of enzymes that modulate the immune response, inflammation, and memory, among many other functions. There are three types of PDEs: cAMP-specific, cGMP-specific, and dual-specific. Here we describe the mechanism of nucleotide selectivity on the basis of high-resolution co-crystal structures of the cAMP-specific PDE4B and PDE4D with AMP, the cGMP-specific PDE5A with GMP, and the apo-structure of the dual-specific PDE1B. These structures show that an invariant glutamine functions as the key specificity determinant by a "glutamine switch" mechanism for recognizing the purine moiety in cAMP or cGMP. The surrounding residues anchor the glutamine residue in different orientations for cAMP and for cGMP. The PDE1B structure shows that in dual-specific PDEs a key histidine residue may enable the invariant glutamine to toggle between cAMP and cGMP. The structural understanding of nucleotide binding enables the design of new PDE inhibitors that may treat diseases in which cyclic nucleotides play a critical role.
 ==About this Structure==
-TBF 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, VIA and GOL as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/3',5'-cyclic-nucleotide_phosphodiesterase 3',5'-cyclic-nucleotide phosphodiesterase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.1.4.17 3.1.4.17] Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1TBF OCA].
+TBF 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>, <scene name='pdbligand=VIA:'>VIA</scene> and <scene name='pdbligand=GOL:'>GOL</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/3',5'-cyclic-nucleotide_phosphodiesterase 3',5'-cyclic-nucleotide phosphodiesterase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.1.4.17 3.1.4.17] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1TBF OCA].
 ==Reference==
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 [[Category: Homo sapiens]]
 [[Category: Single protein]]
-[[Category: Artis, D.R.]]
+[[Category: Artis, D R.]]
 [[Category: Bollag, G.]]
-[[Category: Card, G.L.]]
+[[Category: Card, G L.]]
 [[Category: Fong, D.]]
 [[Category: Gillette, S.]]
 [[Category: Hsieh, D.]]
-[[Category: Kim, S.H.]]
+[[Category: Kim, S H.]]
-[[Category: Milburn, M.V.]]
+[[Category: Milburn, M V.]]
 [[Category: Neiman, J.]]
 [[Category: Schlessinger, J.]]
 [[Category: Suzuki, Y.]]
-[[Category: West, B.L.]]
+[[Category: West, B L.]]
 [[Category: Zhang, C.]]
-[[Category: Zhang, K.Y.J.]]
+[[Category: Zhang, K Y.J.]]
 [[Category: GOL]]
 [[Category: MG]]
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 [[Category: pde5a]]
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