1o5m
From Proteopedia
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'''Structure of FPT bound to the inhibitor SCH66336''' | '''Structure of FPT bound to the inhibitor SCH66336''' | ||
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[[Category: Strickland, C L.]] | [[Category: Strickland, C L.]] | ||
[[Category: Weber, P C.]] | [[Category: Weber, P C.]] | ||
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| - | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 03:25:04 2008'' | |
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Revision as of 00:25, 3 May 2008
Structure of FPT bound to the inhibitor SCH66336
Overview
Crystallographic and thermodynamic studies of farnesyl protein transferase (FPT) complexed with novel tricyclic inhibitors provide insights into the observed SAR for this unique class of nonpeptidic FPT inhibitors. The crystallographic structures reveal a binding pattern conserved across the mono-, di-, and trihalogen series. In the complexes, the tricycle spans the FPT active site cavity and interacts with both protein atoms and the isoprenoid portion of bound farnesyl diphosphate. An amide carbonyl, common to the tricyclic compounds described here, participates in a water-mediated hydrogen bond to the protein backbone. Ten high-resolution crystal structures of inhibitors complexed with FPT are reported. Included are crystallographic data for FPT complexed with SCH 66336, a compound currently undergoing clinical trials as an anticancer agent (SCH 66336, 4-[2-[4-(3,10-dibromo-8-chloro-6,11-dihydro-5H-benzo[5, 6]cyclohepta[1, 2-b]pyridin-11-yl)-1-piperidinyl]-2-oxoethyl]-1-piperidinecarbo xamide ). Thermodynamic binding parameters show favorable enthalpies of complex formation and small net entropic contributions as observed for 4-[2-[4-(3,10-dibromo-8-chloro-6,11-dihydro-11H-benzo[5, 6]cyclohepta[1, 2-b]pyridin-11-ylidene)-1-piperidinyl]-2-oxoethyl]pyridine N-oxide where DeltaH degrees bind = -12.5 kcal/mol and TDeltaS degrees bind = -1.5 kcal/mol.
About this Structure
1O5M is a Protein complex structure of sequences from Rattus norvegicus. Full crystallographic information is available from OCA.
Reference
Tricyclic farnesyl protein transferase inhibitors: crystallographic and calorimetric studies of structure-activity relationships., Strickland CL, Weber PC, Windsor WT, Wu Z, Le HV, Albanese MM, Alvarez CS, Cesarz D, del Rosario J, Deskus J, Mallams AK, Njoroge FG, Piwinski JJ, Remiszewski S, Rossman RR, Taveras AG, Vibulbhan B, Doll RJ, Girijavallabhan VM, Ganguly AK, J Med Chem. 1999 Jun 17;42(12):2125-35. PMID:10377218 Page seeded by OCA on Sat May 3 03:25:04 2008
