4k5f: Difference between revisions
Jump to navigation
Jump to search
No edit summary |
No edit summary |
||
| Line 1: | Line 1: | ||
==Structure of neuronal nitric oxide synthase heme domain in complex with (S)-1,3-bis((2-amino-4-methylpyridin-6-yl)-methoxy)-butan-4-amine== | |||
<StructureSection load='4k5f' size='340' side='right' caption='[[4k5f]], [[Resolution|resolution]] 2.20Å' scene=''> | |||
{ | == Structural highlights == | ||
<table><tr><td colspan='2'>[[4k5f]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Rattus_norvegicus Rattus norvegicus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4K5F OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4K5F FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=H4B:5,6,7,8-TETRAHYDROBIOPTERIN'>H4B</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene>, <scene name='pdbligand=Q14:6-[({(2S)-1-AMINO-4-[(6-AMINO-4-METHYLPYRIDIN-2-YL)METHOXY]BUTAN-2-YL}OXY)METHYL]-4-METHYLPYRIDIN-2-AMINE'>Q14</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> | |||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4k5d|4k5d]], [[4k5e|4k5e]], [[4k5g|4k5g]], [[4k5h|4k5h]], [[4k5i|4k5i]], [[4k5j|4k5j]], [[4k5k|4k5k]]</td></tr> | |||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">Nos1, Bnos ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10116 Rattus norvegicus])</td></tr> | |||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Nitric-oxide_synthase_(NADPH_dependent) Nitric-oxide synthase (NADPH dependent)], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.14.13.39 1.14.13.39] </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=4k5f FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4k5f OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4k5f RCSB], [http://www.ebi.ac.uk/pdbsum/4k5f PDBsum]</span></td></tr> | |||
</table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
To develop potent and selective nNOS inhibitors, new double-headed molecules with chiral linkers that derive from natural amino acids or their derivatives have been designed. The new structures contain two ether bonds, which greatly simplifies the synthesis and accelerates structure optimization. Inhibitor (R)-6b exhibits a potency of 32nM against nNOS and is 475 and 244 more selective for nNOS over eNOS and iNOS, respectively. Crystal structures show that the additional binding between the aminomethyl moiety of 6b and the two heme propionates in nNOS, but not eNOS, is the structural basis for its high selectivity. This work demonstrates the importance of stereochemistry in this class of molecules, which significantly influences the potency and selectivity of the inhibitors. The structure-activity information gathered here provides a guide for future structure optimization. | |||
Chiral linkers to improve selectivity of double-headed neuronal nitric oxide synthase inhibitors.,Jing Q, Li H, Chreifi G, Roman LJ, Martasek P, Poulos TL, Silverman RB Bioorg Med Chem Lett. 2013 Oct 15;23(20):5674-9. doi: 10.1016/j.bmcl.2013.08.034., Epub 2013 Aug 14. PMID:23993333<ref>PMID:23993333</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
== | ==See Also== | ||
*[[Nitric Oxide Synthase|Nitric Oxide Synthase]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Rattus norvegicus]] | [[Category: Rattus norvegicus]] | ||
[[Category: Li, H | [[Category: Li, H]] | ||
[[Category: Poulos, T L | [[Category: Poulos, T L]] | ||
[[Category: Nitric oxide synthase]] | [[Category: Nitric oxide synthase]] | ||
[[Category: Oxidoreductase-oxidoreductase inhibitor complex]] | [[Category: Oxidoreductase-oxidoreductase inhibitor complex]] | ||
Revision as of 17:42, 21 December 2014
Structure of neuronal nitric oxide synthase heme domain in complex with (S)-1,3-bis((2-amino-4-methylpyridin-6-yl)-methoxy)-butan-4-amineStructure of neuronal nitric oxide synthase heme domain in complex with (S)-1,3-bis((2-amino-4-methylpyridin-6-yl)-methoxy)-butan-4-amine
Structural highlights
Publication Abstract from PubMedTo develop potent and selective nNOS inhibitors, new double-headed molecules with chiral linkers that derive from natural amino acids or their derivatives have been designed. The new structures contain two ether bonds, which greatly simplifies the synthesis and accelerates structure optimization. Inhibitor (R)-6b exhibits a potency of 32nM against nNOS and is 475 and 244 more selective for nNOS over eNOS and iNOS, respectively. Crystal structures show that the additional binding between the aminomethyl moiety of 6b and the two heme propionates in nNOS, but not eNOS, is the structural basis for its high selectivity. This work demonstrates the importance of stereochemistry in this class of molecules, which significantly influences the potency and selectivity of the inhibitors. The structure-activity information gathered here provides a guide for future structure optimization. Chiral linkers to improve selectivity of double-headed neuronal nitric oxide synthase inhibitors.,Jing Q, Li H, Chreifi G, Roman LJ, Martasek P, Poulos TL, Silverman RB Bioorg Med Chem Lett. 2013 Oct 15;23(20):5674-9. doi: 10.1016/j.bmcl.2013.08.034., Epub 2013 Aug 14. PMID:23993333[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
|
| ||||||||||||||||||||||