2w1c: Difference between revisions
Jump to navigation
Jump to search
No edit summary |
No edit summary |
||
| Line 1: | Line 1: | ||
==Structure determination of Aurora Kinase in complex with inhibitor== | ==Structure determination of Aurora Kinase in complex with inhibitor== | ||
<StructureSection load='2w1c' size='340' side='right' caption='[[2w1c]], [[Resolution|resolution]] 3.24Å' scene=''> | <StructureSection load='2w1c' size='340' side='right'caption='[[2w1c]], [[Resolution|resolution]] 3.24Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[2w1c]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2W1C OCA]. For a <b>guided tour on the structure components</b> use [http:// | <table><tr><td colspan='2'>[[2w1c]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2W1C OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=2W1C FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=L0C:4-{[2-(4-{[(4-FLUOROPHENYL)CARBONYL]AMINO}-1H-PYRAZOL-3-YL)-1H-BENZIMIDAZOL-6-YL]METHYL}MORPHOLIN-4-IUM'>L0C</scene></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=L0C:4-{[2-(4-{[(4-FLUOROPHENYL)CARBONYL]AMINO}-1H-PYRAZOL-3-YL)-1H-BENZIMIDAZOL-6-YL]METHYL}MORPHOLIN-4-IUM'>L0C</scene></td></tr> | ||
<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=TPO:PHOSPHOTHREONINE'>TPO</scene></td></tr> | <tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=TPO:PHOSPHOTHREONINE'>TPO</scene></td></tr> | ||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1muo|1muo]], [[2j50|2j50]], [[1ol7|1ol7]], [[1ol6|1ol6]], [[2bmc|2bmc]], [[2c6e|2c6e]], [[2j4z|2j4z]], [[1ol5|1ol5]], [[2c6d|2c6d]], [[1mq4|1mq4]], [[2w1g|2w1g]], [[2w1f|2w1f]], [[2w1i|2w1i]], [[2w1d|2w1d]], [[2w1h|2w1h]], [[2w1e|2w1e]]</td></tr> | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1muo|1muo]], [[2j50|2j50]], [[1ol7|1ol7]], [[1ol6|1ol6]], [[2bmc|2bmc]], [[2c6e|2c6e]], [[2j4z|2j4z]], [[1ol5|1ol5]], [[2c6d|2c6d]], [[1mq4|1mq4]], [[2w1g|2w1g]], [[2w1f|2w1f]], [[2w1i|2w1i]], [[2w1d|2w1d]], [[2w1h|2w1h]], [[2w1e|2w1e]]</td></tr> | ||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Non-specific_serine/threonine_protein_kinase Non-specific serine/threonine protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.1 2.7.11.1] </span></td></tr> | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Non-specific_serine/threonine_protein_kinase Non-specific serine/threonine protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.1 2.7.11.1] </span></td></tr> | ||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http:// | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=2w1c FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2w1c OCA], [http://pdbe.org/2w1c PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2w1c RCSB], [http://www.ebi.ac.uk/pdbsum/2w1c PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=2w1c ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Evolutionary Conservation == | == Evolutionary Conservation == | ||
| Line 31: | Line 31: | ||
==See Also== | ==See Also== | ||
*[[Serine/threonine protein kinase|Serine/threonine protein kinase]] | *[[Serine/threonine protein kinase 3D structures|Serine/threonine protein kinase 3D structures]] | ||
== References == | == References == | ||
<references/> | <references/> | ||
| Line 37: | Line 37: | ||
</StructureSection> | </StructureSection> | ||
[[Category: Human]] | [[Category: Human]] | ||
[[Category: Large Structures]] | |||
[[Category: Non-specific serine/threonine protein kinase]] | [[Category: Non-specific serine/threonine protein kinase]] | ||
[[Category: Berdini, V]] | [[Category: Berdini, V]] | ||
Revision as of 11:46, 25 June 2020
Structure determination of Aurora Kinase in complex with inhibitorStructure determination of Aurora Kinase in complex with inhibitor
Structural highlights
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 PubMedHere, we describe the identification of a clinical candidate via structure-based optimization of a ligand efficient pyrazole-benzimidazole fragment. Aurora kinases play a key role in the regulation of mitosis and in recent years have become attractive targets for the treatment of cancer. X-ray crystallographic structures were generated using a novel soakable form of Aurora A and were used to drive the optimization toward potent (IC(50) approximately 3 nM) dual Aurora A/Aurora B inhibitors. These compounds inhibited growth and survival of HCT116 cells and produced the polyploid cellular phenotype typically associated with Aurora B kinase inhibition. Optimization of cellular activity and physicochemical properties ultimately led to the identification of compound 16 (AT9283). In addition to Aurora A and Aurora B, compound 16 was also found to inhibit a number of other kinases including JAK2 and Abl (T315I). This compound demonstrated in vivo efficacy in mouse xenograft models and is currently under evaluation in phase I clinical trials. Fragment-based discovery of the pyrazol-4-yl urea (AT9283), a multitargeted kinase inhibitor with potent aurora kinase activity.,Howard S, Berdini V, Boulstridge JA, Carr MG, Cross DM, Curry J, Devine LA, Early TR, Fazal L, Gill AL, Heathcote M, Maman S, Matthews JE, McMenamin RL, Navarro EF, O'Brien MA, O'Reilly M, Rees DC, Reule M, Tisi D, Williams G, Vinkovic M, Wyatt PG J Med Chem. 2009 Jan 22;52(2):379-88. PMID:19143567[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
|
| ||||||||||||||||||||||
Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)
OCACategories:
- Human
- Large Structures
- Non-specific serine/threonine protein kinase
- Berdini, V
- Boulstridge, J A
- Brien, M A.O
- Carr, M G
- Cross, D M
- Curry, J
- Devine, L A
- Early, T R
- Fazal, L
- Gill, A L
- Heathcote, M
- Howard, S
- Maman, S
- Matthews, J E
- McMenamin, R L
- Navarro, E F
- Rees, D C
- Reilly, M O
- Reule, M
- Tisi, D
- Vinkovic, M
- Williams, G
- Wyatt, P G
- Atp-binding
- Aurora
- Cancer
- Cell cycle
- Inhibitor
- Kinase
- Nucleotide-binding
- Phosphoprotein
- Polymorphism
- Serine/threonine-protein kinase
- Transferase