3i5s Citations

Structural studies of the phosphatidylinositol 3-kinase (PI3K) SH3 domain in complex with a peptide ligand: role of the anchor residue in ligand binding.

Biol. Chem. 391 33-42 (2010)
Cited: 6 times
EuropePMC logo PMID: 19919182

Abstract

Src homology 3 (SH3) domains are mediators of protein-protein interactions. They comprise approximately 60 amino acid residues and are found in many intracellular signaling proteins. Here, we present the crystal structure of the SH3 domain from phosphatidylinositol 3-kinase (PI3K) in complex with the 12-residue proline-rich peptide PD1R (HSKRPLPPLPSL). The crystal structure of the PI3K SH3-PD1R complex at a resolution of 1.7 A reveals type I ligand orientation of the bound peptide with an extended conformation where the central portion forms a left-handed type II polyproline (PPII) helix. The overall structure of the SH3 domain shows minimal changes on ligand binding. In addition, we also attempted crystallization with another peptide ligand (PD1) where the residue at anchor position P(-3) is a tyrosine. The crystals obtained did not contain the PD1 ligand; instead, the ligand binding site is partially occupied by residues Arg18 and Trp55 from the symmetry-related PI3K SH3 molecule. Considering these crystal structures of PI3K SH3 together with published reports, we provide a comparative analysis of protein-ligand interactions that has helped us identify the individual residues which play an important role in defining target specificity.

Reviews citing this publication (2)

  1. Multiple roles for the p85α isoform in the regulation and function of PI3K signalling and receptor trafficking. Mellor P, Furber LA, Nyarko JN, Anderson DH. Biochem. J. 441 23-37 (2012)
  2. Multiple roles for the p85α isoform in the regulation and function of PI3K signalling and receptor trafficking. Mellor P, Furber LA, Nyarko JN, Anderson DH. Biochem. J. 441 23-37 (2012)

Articles citing this publication (4)

  1. High-resolution crystal structure of spectrin SH3 domain fused with a proline-rich peptide. Gushchina LV, Gabdulkhakov AG, Nikonov SV, Filimonov VV. J. Biomol. Struct. Dyn. 29 485-495 (2011)
  2. Regulation of the PI3K pathway through a p85α monomer-homodimer equilibrium. Cheung LW, Walkiewicz KW, Besong TM, Guo H, Hawke DH, Arold ST, Mills GB. Elife 4 e06866 (2015)
  3. Molecular and structural characterization of the SH3 domain of AHI-1 in regulation of cellular resistance of BCR-ABL(+) chronic myeloid leukemia cells to tyrosine kinase inhibitors. Liu X, Chen M, Lobo P, An J, Grace Cheng SW, Moradian A, Morin GB, Van Petegem F, Jiang X. Proteomics 12 2094-2106 (2012)
  4. Assembly and Molecular Architecture of the Phosphoinositide 3-Kinase p85α Homodimer. LoPiccolo J, Kim SJ, Shi Y, Wu B, Wu H, Chait BT, Singer RH, Sali A, Brenowitz M, Bresnick AR, Backer JM. J. Biol. Chem. 290 30390-30405 (2015)