4mrh
From Proteopedia
(Difference between revisions)
| Line 2: | Line 2: | ||
<StructureSection load='4mrh' size='340' side='right' caption='[[4mrh]], [[Resolution|resolution]] 1.12Å' scene=''> | <StructureSection load='4mrh' size='340' side='right' caption='[[4mrh]], [[Resolution|resolution]] 1.12Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
| - | [[4mrh]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4MRH OCA]. <br> | + | <table><tr><td colspan='2'>[[4mrh]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4MRH OCA]. <br> |
| - | <b>[[Ligand|Ligands:]]</b> <scene name='pdbligand=2CQ:4-CHLORO-5-METHYLBENZENE-1,2-DIAMINE'>2CQ</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene><br> | + | </td></tr><tr><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=2CQ:4-CHLORO-5-METHYLBENZENE-1,2-DIAMINE'>2CQ</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene><br> |
| - | <b>[[Related_structure|Related:]]</b> [[4mrd|4mrd]], [[4mre|4mre]], [[4mrf|4mrf]], [[4mrg|4mrg]], [[4np2|4np2]], [[4np3|4np3]]< | + | <tr><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4mrd|4mrd]], [[4mre|4mre]], [[4mrf|4mrf]], [[4mrg|4mrg]], [[4np2|4np2]], [[4np3|4np3]]</td></tr> |
| - | <b>Activity:</b> <span class='plainlinks'>[http://en.wikipedia.org/wiki/Glucokinase Glucokinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.1.2 2.7.1.2] </span>< | + | <tr><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Glucokinase Glucokinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.1.2 2.7.1.2] </span></td></tr> |
| - | <b>Resources:</b> <span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4mrh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4mrh OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4mrh RCSB], [http://www.ebi.ac.uk/pdbsum/4mrh PDBsum]</span>< | + | <tr><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4mrh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4mrh OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4mrh RCSB], [http://www.ebi.ac.uk/pdbsum/4mrh PDBsum]</span></td></tr> |
| + | <table> | ||
| + | <div style="background-color:#fffaf0;"> | ||
== Publication Abstract from PubMed == | == Publication Abstract from PubMed == | ||
Selective inhibitors of hyaluronan (HA) binding to the cell surface receptor CD44 will have value as probes of CD44-mediated signaling and have potential as therapeutic agents in chronic inflammation, cardiovascular disease, and cancer. Using biophysical binding assays, fragment screening, and crystallographic characterization of complexes with the CD44 HA binding domain, we have discovered an inducible pocket adjacent to the HA binding groove into which small molecules may bind. Iterations of fragment combination and structure-driven design have allowed identification of a series of 1,2,3,4-tetrahydroisoquinolines as the first nonglycosidic inhibitors of the CD44-HA interaction. The affinity of these molecules for the CD44 HA binding domain parallels their ability to interfere with CD44 binding to polymeric HA in vitro. X-ray crystallographic complexes of lead compounds are described and compared to a new complex with a short HA tetrasaccharide, to establish the tetrahydroisoquinoline pharmacophore as an attractive starting point for lead optimization. | Selective inhibitors of hyaluronan (HA) binding to the cell surface receptor CD44 will have value as probes of CD44-mediated signaling and have potential as therapeutic agents in chronic inflammation, cardiovascular disease, and cancer. Using biophysical binding assays, fragment screening, and crystallographic characterization of complexes with the CD44 HA binding domain, we have discovered an inducible pocket adjacent to the HA binding groove into which small molecules may bind. Iterations of fragment combination and structure-driven design have allowed identification of a series of 1,2,3,4-tetrahydroisoquinolines as the first nonglycosidic inhibitors of the CD44-HA interaction. The affinity of these molecules for the CD44 HA binding domain parallels their ability to interfere with CD44 binding to polymeric HA in vitro. X-ray crystallographic complexes of lead compounds are described and compared to a new complex with a short HA tetrasaccharide, to establish the tetrahydroisoquinoline pharmacophore as an attractive starting point for lead optimization. | ||
| Line 13: | Line 15: | ||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
== References == | == References == | ||
<references/> | <references/> | ||
Revision as of 09:27, 1 May 2014
Crystal structure of the murine CD44 hyaluronan binding domain complex with a small molecule
| |||||||||||
