1zkl

From Proteopedia

(Difference between revisions)

Revision as of 09:07, 2 May 2018

Multiple Determinants for Inhibitor Selectivity of Cyclic Nucleotide Phosphodiesterases

Structural highlights

1zkl is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, ,
Gene:	PDE7A (HUMAN)
Activity:	3',5'-cyclic-nucleotide phosphodiesterase, with EC number 3.1.4.17
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[PDE7A_HUMAN] Hydrolyzes the second messenger cAMP, which is a key regulator of many important physiological processes. May have a role in muscle signal transduction.^[1]

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

Phosphodiesterase (PDE) inhibitors have been widely studied as therapeutics for treatment of human diseases. However, the mechanism by which each PDE family recognizes selectively a category of inhibitors remains a puzzle. Here we report the crystal structure of PDE7A1 catalytic domain in complex with non-selective inhibitor 3-isobutyl-1-methylxanthine and kinetic analysis on the mutants of PDE7A1 and PDE4D2. Our studies suggest at least three elements play critical roles in inhibitor selectivity: 1) the conformation and position of an invariant glutamine, 2) the natures of scaffolding residues, and 3) residues that alter shape and size of the binding pocket. Kinetic analysis shows that single PDE7 to PDE4 mutations increase the sensitivity of PDE7 to PDE4 inhibitors but are not sufficient to render the engineered enzymes comparable with the wild types. The triple S373Y/S377T/I412S mutation of PDE7A1 produces a PDE4-like enzyme, implying that multiple elements must work together to determine inhibitor selectivity.

Multiple elements jointly determine inhibitor selectivity of cyclic nucleotide phosphodiesterases 4 and 7.,Wang H, Liu Y, Chen Y, Robinson H, Ke H J Biol Chem. 2005 Sep 2;280(35):30949-55. Epub 2005 Jul 1. PMID:15994308^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Castano T, Wang H, Campillo NE, Ballester S, Gonzalez-Garcia C, Hernandez J, Perez C, Cuenca J, Perez-Castillo A, Martinez A, Huertas O, Gelpi JL, Luque FJ, Ke H, Gil C. Synthesis, Structural Analysis, and Biological Evaluation of Thioxoquinazoline Derivatives as Phosphodiesterase 7 Inhibitors. ChemMedChem. 2009 Apr 6. PMID:19350606 doi:10.1002/cmdc.200900043
↑ Wang H, Liu Y, Chen Y, Robinson H, Ke H. Multiple elements jointly determine inhibitor selectivity of cyclic nucleotide phosphodiesterases 4 and 7. J Biol Chem. 2005 Sep 2;280(35):30949-55. Epub 2005 Jul 1. PMID:15994308 doi:http://dx.doi.org/10.1074/jbc.M504398200

1 Structural highlights
2 Function
3 Evolutionary Conservation
4 Publication Abstract from PubMed
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/1zkl"

@@ Line 1: / Line 1: @@
 ==Multiple Determinants for Inhibitor Selectivity of Cyclic Nucleotide Phosphodiesterases==
 <StructureSection load='1zkl' size='340' side='right' caption='[[1zkl]], [[Resolution|resolution]] 1.67&Aring;' scene=''>
@@ Line 6: / Line 7: @@
 <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">PDE7A ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
 <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[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] </span></td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1zkl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1zkl OCA], [http://pdbe.org/1zkl PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=1zkl RCSB], [http://www.ebi.ac.uk/pdbsum/1zkl PDBsum]</span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1zkl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1zkl OCA], [http://pdbe.org/1zkl PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=1zkl RCSB], [http://www.ebi.ac.uk/pdbsum/1zkl PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=1zkl ProSAT]</span></td></tr>
 </table>
 == Function ==
@@ Line 14: / Line 15: @@
 Check<jmol>
   <jmolCheckbox>
-    <scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/zk/1zkl_consurf.spt"</scriptWhenChecked>
+    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/zk/1zkl_consurf.spt"</scriptWhenChecked>
     <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
     <text>to colour the structure by Evolutionary Conservation</text>
@@ Line 29: / Line 30: @@
 </div>
 <div class="pdbe-citations 1zkl" style="background-color:#fffaf0;"></div>
-==See Also==
-*[[Phosphodiesterase|Phosphodiesterase]]
 == References ==
 <references/>

1zkl

From Proteopedia

Revision as of 09:07, 2 May 2018

Multiple Determinants for Inhibitor Selectivity of Cyclic Nucleotide Phosphodiesterases

Structural highlights

Function

Evolutionary Conservation

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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