4msh: Difference between revisions
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<StructureSection load='4msh' size='340' side='right' caption='[[4msh]], [[Resolution|resolution]] 2.30Å' scene=''> | <StructureSection load='4msh' size='340' side='right' caption='[[4msh]], [[Resolution|resolution]] 2.30Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[4msh]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4MSH OCA]. <br> | <table><tr><td colspan='2'>[[4msh]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4MSH OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4MSH FirstGlance]. <br> | ||
</td></tr><tr><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=2D0:4-CHLORO-1,3-BENZOTHIAZOL-2-AMINE'>2D0</scene>, <scene name='pdbligand=NI:NICKEL+(II)+ION'>NI</scene>< | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=2D0:4-CHLORO-1,3-BENZOTHIAZOL-2-AMINE'>2D0</scene>, <scene name='pdbligand=NI:NICKEL+(II)+ION'>NI</scene></td></tr> | ||
<tr><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4mrw|4mrw]], [[4mrz|4mrz]], [[4ms0|4ms0]], [[4msa|4msa]], [[4msc|4msc]], [[4mse|4mse]], [[4msn|4msn]]</td></tr> | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4mrw|4mrw]], [[4mrz|4mrz]], [[4ms0|4ms0]], [[4msa|4msa]], [[4msc|4msc]], [[4mse|4mse]], [[4msn|4msn]]</td></tr> | ||
<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=4msh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4msh OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4msh RCSB], [http://www.ebi.ac.uk/pdbsum/4msh PDBsum]</span></td></tr> | ||
</table> | |||
<table> | == Function == | ||
[[http://www.uniprot.org/uniprot/PDE10_HUMAN PDE10_HUMAN]] Plays a role in signal transduction by regulating the intracellular concentration of cyclic nucleotides. Can hydrolyze both cAMP and cGMP, but has higher affinity for cAMP and is more efficient with cAMP as substrate.<ref>PMID:17389385</ref> | |||
<div style="background-color:#fffaf0;"> | <div style="background-color:#fffaf0;"> | ||
== Publication Abstract from PubMed == | == Publication Abstract from PubMed == | ||
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Identification and Optimization of PDE10A Inhibitors Using Fragment-Based Screening by Nanocalorimetry and X-ray Crystallography.,Recht MI, Sridhar V, Badger J, Bounaud PY, Logan C, Chie-Leon B, Nienaber V, Torres FE J Biomol Screen. 2013 Dec 27. PMID:24375910<ref>PMID:24375910</ref> | Identification and Optimization of PDE10A Inhibitors Using Fragment-Based Screening by Nanocalorimetry and X-ray Crystallography.,Recht MI, Sridhar V, Badger J, Bounaud PY, Logan C, Chie-Leon B, Nienaber V, Torres FE J Biomol Screen. 2013 Dec 27. PMID:24375910<ref>PMID:24375910</ref> | ||
From | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
</div> | </div> | ||
== References == | == References == | ||
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__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Badger, J | [[Category: Badger, J]] | ||
[[Category: Chie-Leon, B | [[Category: Chie-Leon, B]] | ||
[[Category: Logan, C | [[Category: Logan, C]] | ||
[[Category: Nienaber, V | [[Category: Nienaber, V]] | ||
[[Category: Sridhar, V | [[Category: Sridhar, V]] | ||
[[Category: Fragment screening]] | [[Category: Fragment screening]] | ||
[[Category: Hydrolase]] | [[Category: Hydrolase]] | ||
[[Category: Hydrolase-hydrolase inhibitor complex]] | [[Category: Hydrolase-hydrolase inhibitor complex]] | ||
Revision as of 09:46, 25 December 2014
Crystal Structure of PDE10A2 with fragment ZT0143 ((2S)-4-chloro-2,3-dihydro-1,3-benzothiazol-2-amine)Crystal Structure of PDE10A2 with fragment ZT0143 ((2S)-4-chloro-2,3-dihydro-1,3-benzothiazol-2-amine)
Structural highlights
Function[PDE10_HUMAN] Plays a role in signal transduction by regulating the intracellular concentration of cyclic nucleotides. Can hydrolyze both cAMP and cGMP, but has higher affinity for cAMP and is more efficient with cAMP as substrate.[1] Publication Abstract from PubMedFragment-based lead discovery (FBLD) is a technique in which small, low-complexity chemical fragments of 6 to 15 heavy atoms are screened for binding to or inhibiting activity of the target. Hits are then linked and/or elaborated into tightly binding ligands, ideally yielding early lead compounds for drug discovery. Calorimetry provides a label-free method to assay binding and enzymatic activity that is unaffected by the spectroscopic properties of the sample. Conventional microcalorimetry is hampered by requiring large quantities of reagents and long measurement times. Nanocalorimeters can overcome these limitations of conventional isothermal titration calorimetry. Here we use enthalpy arrays, which are arrays of nanocalorimeters, to perform an enzyme activity-based fragment screen for competitive inhibitors of phosphodiesterase 10A (PDE10A). Two dozen fragments with KI <2 mM were identified and moved to crystal soaking trials. All soak experiments yielded high-resolution diffraction, with two-thirds of the fragments yielding high-resolution co-crystal structures with PDE10A. The structural information was used to elaborate fragment hits, yielding leads with KI <1 microM. This study shows how array calorimetry can be used as a prescreening method for fragment-based lead discovery with enzyme targets and paired successfully with an X-ray crystallography secondary screen. Identification and Optimization of PDE10A Inhibitors Using Fragment-Based Screening by Nanocalorimetry and X-ray Crystallography.,Recht MI, Sridhar V, Badger J, Bounaud PY, Logan C, Chie-Leon B, Nienaber V, Torres FE J Biomol Screen. 2013 Dec 27. PMID:24375910[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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