5TB5

Crystal structure of full-length farnesylated and methylated KRAS4b in complex with PDE-delta (crystal form I - with partially disordered hypervariable region)

5TB5 の概要

• エントリーDOI: 10.2210/pdb5tb5/pdb
• 分子名称: GTPase KRas, Retinal rod rhodopsin-sensitive cGMP 3',5'-cyclic phosphodiesterase subunit delta, FARNESYL, ... (6 entities in total)
• 機能のキーワード: kras4b, pdedelta, pde6delta, ras, kras, oncoprotein
• 由来する生物種: Homo sapiens (Human); 詳細
• 細胞内の位置: Cell membrane ; Lipid-anchor ; Cytoplasmic side : P01116; Cytoplasm, cytosol : O43924
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 78417.26

構造登録者

Dharmaiah, S.,Tran, T.H.,Simanshu, D.K. (登録日: 2016-09-11, 公開日: 2016-11-02, 最終更新日: 2023-10-04)

主引用文献

Dharmaiah, S.,Bindu, L.,Tran, T.H.,Gillette, W.K.,Frank, P.H.,Ghirlando, R.,Nissley, D.V.,Esposito, D.,McCormick, F.,Stephen, A.G.,Simanshu, D.K.
Structural basis of recognition of farnesylated and methylated KRAS4b by PDE delta.
Proc.Natl.Acad.Sci.USA, 113:E6766-E6775, 2016

PubMed Abstract: Farnesylation and carboxymethylation of KRAS4b (Kirsten rat sarcoma isoform 4b) are essential for its interaction with the plasma membrane where KRAS-mediated signaling events occur. Phosphodiesterase-δ (PDEδ) binds to KRAS4b and plays an important role in targeting it to cellular membranes. We solved structures of human farnesylated-methylated KRAS4b in complex with PDEδ in two different crystal forms. In these structures, the interaction is driven by the C-terminal amino acids together with the farnesylated and methylated C185 of KRAS4b that binds tightly in the central hydrophobic pocket present in PDEδ. In crystal form II, we see the full-length structure of farnesylated-methylated KRAS4b, including the hypervariable region. Crystal form I reveals structural details of farnesylated-methylated KRAS4b binding to PDEδ, and crystal form II suggests the potential binding mode of geranylgeranylated-methylated KRAS4b to PDEδ. We identified a 5-aa-long sequence motif (Lys-Ser-Lys-Thr-Lys) in KRAS4b that may enable PDEδ to bind both forms of prenylated KRAS4b. Structure and sequence analysis of various prenylated proteins that have been previously tested for binding to PDEδ provides a rationale for why some prenylated proteins, such as KRAS4a, RalA, RalB, and Rac1, do not bind to PDEδ. Comparison of all four available structures of PDEδ complexed with various prenylated proteins/peptides shows the presence of additional interactions due to a larger protein-protein interaction interface in KRAS4b-PDEδ complex. This interface might be exploited for designing an inhibitor with minimal off-target effects.

PubMed: 27791178
DOI: 10.1073/pnas.1615316113

実験手法

X-RAY DIFFRACTION (2 Å)