1O5M

Structure of FPT bound to the inhibitor SCH66336

Summary for 1O5M

• Entry DOI: 10.2210/pdb1o5m/pdb
• Related: 1QBQ
• Descriptor: Protein farnesyltransferase alpha subunit, Protein farnesyltransferase beta subunit, ZINC ION, ... (6 entities in total)
• Functional Keywords: protein inhibitor complex, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Rattus norvegicus (Norway rat); More
• Total number of polymer chains: 2
• Total formula weight: 93894.93

Authors

Strickland, C.L.,Weber, P.C.,Ganguly, A.K. (deposition date: 2003-09-26, release date: 2003-10-21, Last modification date: 2023-12-27)

Primary citation

Strickland, C.L.,Weber, P.C.,Windsor, W.T.,Wu, Z.,Le, H.V.,Albanese, M.M.,Alvarez, C.S.,Cesarz, D.,del Rosario, J.,Deskus, J.,Mallams, A.K.,Njoroge, F.G.,Piwinski, J.J.,Remiszewski, S.,Rossman, R.R.,Taveras, A.G.,Vibulbhan, B.,Doll, R.J.,Girijavallabhan, V.M.,Ganguly, A.K.
Tricyclic Farnesyl Protein Transferase Inhibitors: Crystallographic and Calorimetric Studies of Structure-Activity Relationships
J.Med.Chem., 42:2125-2135, 1999

PubMed Abstract: 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.

PubMed: 10377218
DOI: 10.1021/jm990030g

Experimental method

X-RAY DIFFRACTION (2.3 Å)