1ld8
From Proteopedia
(New page: 200px<br /> <applet load="1ld8" size="450" color="white" frame="true" align="right" spinBox="true" caption="1ld8, resolution 1.80Å" /> '''Co-crystal structur...) |
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| - | [[Image:1ld8. | + | [[Image:1ld8.jpg|left|200px]]<br /><applet load="1ld8" size="350" color="white" frame="true" align="right" spinBox="true" |
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caption="1ld8, resolution 1.80Å" /> | caption="1ld8, resolution 1.80Å" /> | ||
'''Co-crystal structure of Human Farnesyltransferase with farnesyldiphosphate and inhibitor compound 49'''<br /> | '''Co-crystal structure of Human Farnesyltransferase with farnesyldiphosphate and inhibitor compound 49'''<br /> | ||
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==About this Structure== | ==About this Structure== | ||
| - | 1LD8 is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with SUC, ZN, FPP, U49 and ACY as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http:// | + | 1LD8 is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=SUC:'>SUC</scene>, <scene name='pdbligand=ZN:'>ZN</scene>, <scene name='pdbligand=FPP:'>FPP</scene>, <scene name='pdbligand=U49:'>U49</scene> and <scene name='pdbligand=ACY:'>ACY</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1LD8 OCA]. |
==Reference== | ==Reference== | ||
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[[Category: ras]] | [[Category: ras]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Fri Feb 15 16:17:34 2008'' |
Revision as of 14:17, 15 February 2008
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Co-crystal structure of Human Farnesyltransferase with farnesyldiphosphate and inhibitor compound 49
Overview
A series of macrocyclic 3-aminopyrrolidinone farnesyltransferase, inhibitors (FTIs) has been synthesized. Compared with previously described, linear 3-aminopyrrolidinone FTIs such as compound 1, macrocycles such as, 49 combined improved pharmacokinetic properties with a reduced potential, for side effects. In dogs, oral bioavailability was good to excellent, and, increases in plasma half-life were due to attenuated clearance. It was, observed that in vivo clearance correlated with the flexibility of the, molecules and this concept proved useful in the design of FTIs that, exhibited low clearance, such as FTI 78. X-ray crystal structures of, compounds 49 and 66 complexed with farnesyltransferase (FTase)-farnesyl, diphosphate (FPP) were determined, and they provide details of the key, interactions in such ternary complexes. Optimization of this, 3-aminopyrrolidinone series of compounds led to significant increases in, potency, providing 83 and 85, the most potent inhibitors of FTase in cells, described to date.
About this Structure
1LD8 is a Protein complex structure of sequences from Homo sapiens with , , , and as ligands. Full crystallographic information is available from OCA.
Reference
3-Aminopyrrolidinone farnesyltransferase inhibitors: design of macrocyclic compounds with improved pharmacokinetics and excellent cell potency., Bell IM, Gallicchio SN, Abrams M, Beese LS, Beshore DC, Bhimnathwala H, Bogusky MJ, Buser CA, Culberson JC, Davide J, Ellis-Hutchings M, Fernandes C, Gibbs JB, Graham SL, Hamilton KA, Hartman GD, Heimbrook DC, Homnick CF, Huber HE, Huff JR, Kassahun K, Koblan KS, Kohl NE, Lobell RB, Lynch JJ Jr, Robinson R, Rodrigues AD, Taylor JS, Walsh ES, Williams TM, Zartman CB, J Med Chem. 2002 Jun 6;45(12):2388-409. PMID:12036349
Page seeded by OCA on Fri Feb 15 16:17:34 2008
Categories: Homo sapiens | Protein complex | Beese, L.S. | Taylor, J.S. | Terry, K.L. | ACY | FPP | SUC | U49 | ZN | Alpha-alpha barrel | Caax | Fpp | Ftase | Inhibitor | Pftase | Ras
