1O5M

Structure of FPT bound to the inhibitor SCH66336

1O5M の概要

• エントリーDOI: 10.2210/pdb1o5m/pdb
• 関連するPDBエントリー: 1QBQ
• 分子名称: Protein farnesyltransferase alpha subunit, Protein farnesyltransferase beta subunit, ZINC ION, ... (6 entities in total)
• 機能のキーワード: protein inhibitor complex, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Rattus norvegicus (Norway rat); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 93894.93

構造登録者

Strickland, C.L.,Weber, P.C.,Ganguly, A.K. (登録日: 2003-09-26, 公開日: 2003-10-21, 最終更新日: 2023-12-27)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.3 Å)