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

Batra-Safferling R, Granzin J, Mödder S, Hoffmann S, Willbold D
Biol Chem 391 33-42 (2010)
Cited: 14 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.

Articles - 3i5s mentioned but not cited (6)

  1. 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)
  2. Binding-induced folding under unfolding conditions: Switching between induced fit and conformational selection mechanisms. Sen S, Udgaonkar JB. J Biol Chem 294 16942-16952 (2019)
  3. Integrated Network Pharmacology Analysis and Experimental Validation to Investigate the Molecular Mechanism of Triptolide in the Treatment of Membranous Nephropathy. Zhang PN, Tang JY, Yang KZ, Zheng QY, Dong ZC, Geng YL, Liu YN, Liu WJ. Drug Des Devel Ther 16 4061-4076 (2022)
  4. Mechanism of baixiangdan capsules on anti-neuroinflammation: combining dry and wet experiments. Yu Q, Liu M, Zhao T, Su M, Wang S, Xu W, He S, Li K, Mu X, Wu J, Sun P, Zheng F, Weng N. Aging (Albany NY) 15 7689-7708 (2023)
  5. Protective Effect of Hedyotis diffusa Willd. Ethanol Extract on Isoniazid-Induced Liver Injury in the Zebrafish Model. Wang X, Zhao J, Zhang R, Liu X, Ma C, Cao G, Wei Y, Yang P. Drug Des Devel Ther 16 1995-2015 (2022)
  6. The Molecular Mechanisms of Panax ginseng in Treating Type 2 Diabetes Mellitus: Network Pharmacology Analysis and Molecular Docking Validation. Tran MN, Lee S. Evid Based Complement Alternat Med 2022 3082109 (2022)


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. Amyloidogenesis: What Do We Know So Far? Alraawi Z, Banerjee N, Mohanty S, Kumar TKS. Int J Mol Sci 23 13970 (2022)

Articles citing this publication (6)

  1. 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)
  2. Atomic structure of PI3-kinase SH3 amyloid fibrils by cryo-electron microscopy. Röder C, Vettore N, Mangels LN, Gremer L, Ravelli RBG, Willbold D, Hoyer W, Buell AK, Schröder GF. Nat Commun 10 3754 (2019)
  3. Patient-derived mutations within the N-terminal domains of p85α impact PTEN or Rab5 binding and regulation. Mellor P, Marshall JDS, Ruan X, Whitecross DE, Ross RL, Knowles MA, Moore SA, Anderson DH. Sci Rep 8 7108 (2018)
  4. 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)
  5. 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)
  6. Amyloid fibril formation kinetics of low-pH denatured bovine PI3K-SH3 monitored by three different NMR techniques. Gardon L, Becker N, Rähse N, Hölbling C, Apostolidis A, Schulz CM, Bochinsky K, Gremer L, Heise H, Lakomek NA. Front Mol Biosci 10 1254721 (2023)


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