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==Crystal structure of the murine CD44 hyaluronan binding domain complex with a small molecule== | ==Crystal structure of the murine CD44 hyaluronan binding domain complex with a small molecule== | ||
<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 with sequence from [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4MRH OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4MRH FirstGlance]. <br> | ||
< | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.12Å</td></tr> | ||
<b> | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=2CQ:4-CHLORO-5-METHYLBENZENE-1,2-DIAMINE'>2CQ</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene></td></tr> | ||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4mrh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4mrh OCA], [https://pdbe.org/4mrh PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4mrh RCSB], [https://www.ebi.ac.uk/pdbsum/4mrh PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4mrh ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/CD44_MOUSE CD44_MOUSE] Main cell surface receptor for hyaluronate. Adhesion to mucosal high endothelial venule and to types I and VI collagen. Probably involved in matrix adhesion, lymphocyte activation and lymph node homing. | |||
<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. | ||
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Fragment-Based Identification of an Inducible Binding Site on Cell Surface Receptor CD44 for the Design of Protein-Carbohydrate Interaction Inhibitors.,Liu LK, Finzel BC J Med Chem. 2014 Mar 27;57(6):2714-25. doi: 10.1021/jm5000276. Epub 2014 Mar 7. PMID:24606063<ref>PMID:24606063</ref> | Fragment-Based Identification of an Inducible Binding Site on Cell Surface Receptor CD44 for the Design of Protein-Carbohydrate Interaction Inhibitors.,Liu LK, Finzel BC J Med Chem. 2014 Mar 27;57(6):2714-25. doi: 10.1021/jm5000276. Epub 2014 Mar 7. PMID:24606063<ref>PMID:24606063</ref> | ||
From | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
</div> | |||
<div class="pdbe-citations 4mrh" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[CD44|CD44]] | |||
== References == | == References == | ||
<references/> | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: | [[Category: Large Structures]] | ||
[[Category: | [[Category: Mus musculus]] | ||
[[Category: | [[Category: Finzel B]] | ||
[[Category: | [[Category: Liu LK]] | ||
Latest revision as of 19:41, 20 September 2023
Crystal structure of the murine CD44 hyaluronan binding domain complex with a small moleculeCrystal structure of the murine CD44 hyaluronan binding domain complex with a small molecule
Structural highlights
FunctionCD44_MOUSE Main cell surface receptor for hyaluronate. Adhesion to mucosal high endothelial venule and to types I and VI collagen. Probably involved in matrix adhesion, lymphocyte activation and lymph node homing. Publication Abstract from PubMedSelective 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. Fragment-Based Identification of an Inducible Binding Site on Cell Surface Receptor CD44 for the Design of Protein-Carbohydrate Interaction Inhibitors.,Liu LK, Finzel BC J Med Chem. 2014 Mar 27;57(6):2714-25. doi: 10.1021/jm5000276. Epub 2014 Mar 7. PMID:24606063[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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