2g1q
From Proteopedia
(New page: 200px<br /> <applet load="2g1q" size="450" color="white" frame="true" align="right" spinBox="true" caption="2g1q, resolution 2.51Å" /> '''crystal structure o...) |
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| - | [[Image:2g1q.gif|left|200px]]<br /> | + | [[Image:2g1q.gif|left|200px]]<br /><applet load="2g1q" size="350" color="white" frame="true" align="right" spinBox="true" |
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caption="2g1q, resolution 2.51Å" /> | caption="2g1q, resolution 2.51Å" /> | ||
'''crystal structure of KSP in complex with inhibitor 9h'''<br /> | '''crystal structure of KSP in complex with inhibitor 9h'''<br /> | ||
==Overview== | ==Overview== | ||
| - | Molecular modeling in combination with X-ray crystallographic information | + | Molecular modeling in combination with X-ray crystallographic information was employed to identify a region of the kinesin spindle protein (KSP) binding site not fully utilized by our first generation inhibitors. We discovered that by appending a propylamine substituent at the C5 carbon of a dihydropyrazole core, we could effectively fill this unoccupied region of space and engage in a hydrogen-bonding interaction with the enzyme backbone. This change led to a second generation compound with increased potency, a 400-fold enhancement in aqueous solubility at pH 4, and improved dog pharmacokinetics relative to the first generation compound. |
==About this Structure== | ==About this Structure== | ||
| - | 2G1Q is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with MG, ADP and N9H as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http:// | + | 2G1Q is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=MG:'>MG</scene>, <scene name='pdbligand=ADP:'>ADP</scene> and <scene name='pdbligand=N9H:'>N9H</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2G1Q OCA]. |
==Reference== | ==Reference== | ||
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[[Category: ksp-inhibitor complex]] | [[Category: ksp-inhibitor complex]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 17:27:17 2008'' |
Revision as of 15:27, 21 February 2008
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crystal structure of KSP in complex with inhibitor 9h
Overview
Molecular modeling in combination with X-ray crystallographic information was employed to identify a region of the kinesin spindle protein (KSP) binding site not fully utilized by our first generation inhibitors. We discovered that by appending a propylamine substituent at the C5 carbon of a dihydropyrazole core, we could effectively fill this unoccupied region of space and engage in a hydrogen-bonding interaction with the enzyme backbone. This change led to a second generation compound with increased potency, a 400-fold enhancement in aqueous solubility at pH 4, and improved dog pharmacokinetics relative to the first generation compound.
About this Structure
2G1Q is a Single protein structure of sequence from Homo sapiens with , and as ligands. Full crystallographic information is available from OCA.
Reference
Kinesin spindle protein (KSP) inhibitors. Part 4: Structure-based design of 5-alkylamino-3,5-diaryl-4,5-dihydropyrazoles as potent, water-soluble inhibitors of the mitotic kinesin KSP., Cox CD, Torrent M, Breslin MJ, Mariano BJ, Whitman DB, Coleman PJ, Buser CA, Walsh ES, Hamilton K, Schaber MD, Lobell RB, Tao W, South VJ, Kohl NE, Yan Y, Kuo LC, Prueksaritanont T, Slaughter DE, Li C, Mahan E, Lu B, Hartman GD, Bioorg Med Chem Lett. 2006 Jun 15;16(12):3175-9. Epub 2006 Apr 5. PMID:16603356
Page seeded by OCA on Thu Feb 21 17:27:17 2008
Categories: Homo sapiens | Single protein | Yan, Y. | ADP | MG | N9H | Ksp | Ksp-inhibitor complex
