PI3K-alpha Catalytic Subunit - 3D Mechanism Simulator

Loading structural data… (2RD0)

References & Databases

START HERE — how to read PIP2 + ATP → PIP3 + ADP A single lipid-kinase cartoon on the human p110α/p85α frame that exists: 2RD0 (3.05 Å), chain A, with p85α chain B. The deposit is apo — no nucleotide and no PIP2. ATP and the PIP2 analog are [schematic]. PIP3 and ADP are [schematic]. Asp933 is the compiled lipid 3-OH proton acceptor. Gold H⁺ parks on Asp933; blue is the Ins-3-OH nucleophile, not a hydride; the γ-phosphate rides off ATP onto the inositol O3 (an in-line transfer that inverts the configuration at P). p85α is named occupancy, not a swing. His1047 is oncogenic, named, not the nucleophile. Overlay lipid distances are not geomClaims. 4JPS inhibitor 1LT is a named overlay only, not this mesh. PIK3CB / PIK3CG / PIK3CD are other genes.
Crystal structures PDB 2RD0 — human p110α/p85α, 3.05 Å (Huang 2007). Coordinates are public. Apo — no nucleotide. 4JPS holds inhibitor 1LT — named overlay only, not this mesh. 3HHM wortmannin is not this mesh.
Mechanism — Asp933 base, in-line γ-PO₃ onto Ins-3-OH Huang et al., Science 2007, PMID:18079394 — p110α/p85α structure and oncogenic mutations. UniProt P42336 has no ACT_SITE for the lipid 3-OH; Asp933 is the compiled DFG-adjacent base. Lys802 orients ATP. Product is PtdIns(3,4,5)P₃, not a protein phosphate. UniProt P42336 lists EC 2.7.1.137 + 2.7.1.153; a separate protein-kinase activity (EC 2.7.11.1) is reported for PI3K but is not a UniProt-assigned EC — named, not shown. Source: Huang 2007 · UniProt P42336
0 — Setup: empty ATP/PIP2 cleft, p85 stays 2RD0 holds p110α and p85α. The cleft is shown empty so ordered binding can start. p85α stays visible as named occupancy. Opaque, no autoplay. Chemistry below uses schematic ATP + PIP2. Lys802 NZ ⋯ Asp805 OD2 = 2.58 Å on this deposit.Source: PDB 2RD0
① — PIP2 analog presented A short PtdIns(4,5)P₂ analog docks as a named stand-in for membrane PIP2 — [schematic], not a crystal lipid. Ins 3-OH (O3) faces the ATP site. Overlay lipid Å are not geomClaims.Source: compiled PI3K substrate identity · UniProt P42336
② — Schematic ATP docks Schematic ATP and schematic Mg dock into the apo cleft — ATP is [schematic], not a 4JPS drug relabeled. Lys802 NZ ⋯ Asp805 OD2 = 2.58 Å is deposited 2RD0 (protein, not a ligand claim). Overlay ATP / PIP2 distances are not geomClaims.Source: 2RD0 protein pose · schematic ATP
③ — Asp933 deprotonates the Ins-3-OH (hypothetical, lit.-based) A gold H⁺ sphere rides a gold arrow from PIP2 O3 to Asp933 OD2 and parks. Compiled kinase writes this proton transfer with the γ-PO₃ transfer; this page splits them. Asp933 is compiled, not a UniProt ACT_SITE.Source: compiled lipid 3-OH base · UniProt P42336
④ — In-line γ-PO₃ transfer → PIP3 (hypothetical, lit.-based) The Ins-3-OH oxygen (blue) attacks ATP γ-P (PG) in line. In slow motion the γ-phosphate itself rides off ATP onto the inositol O3 — it is not teleported: the PO₃ group crosses onto the lipid across the same window the arrow spans, so PIP2 gains the 3-phosphate (PIP3) as ADP loses it. This is an associative in-line phosphoryl transfer that inverts the configuration at P (an umbrella flip — the γ-phosphate itself turns over 180°, and the purple equatorial TS rig's tick sweeps 180°, on the in-line O3⋯P⋯O3B axis). PIP2 + ATP then fade in place to schematic PIP3 and schematic ADP. Parked gold H⁺ stays on Asp933. Overlay phospho-lipid contacts are not geomClaims. Slow-motion on purpose. No covalent phospho-enzyme.Source: compiled PI3K kinase · UniProt P42336
⑤ — Products leave — p85 stays [schematic] PIP3 and ADP·Mg depart in opposite directions. Parked gold H⁺ leaves toward solvent. p85α stays. PTEN removes this 3-phosphate on another page.Source: EC 2.7.1.153 net accounting

How to read this page — a first-pass primer First pass: Setup (apo cleft empty, p85 stays, Asp933 ★) → ① PIP2 analog docks → ② schematic ATP+Mg dock → ③ gold H⁺ O3 → Asp933 (parks) → ④ slow-mo: the blue arrow marks the in-line attack (O3 → γ-P) and the γ-phosphate rides off ATP onto the inositol O3 (it moves across the window — no teleport), then PIP2+ATP become PIP3+ADP → ⑤ products leave; p85 stays. Second pass: 2.58 / 3.23 / 3.27 / 3.59 Å are crystal protein facts on 2RD0; ATP, PIP2, PIP3, ADP, Mg, and the H spheres are [schematic]. Third pass: open “Disagreements” for apo vs ATP, analog vs membrane PIP2, 4JPS 1LT, PIK3CB/G/D, and concerted vs split.
Chemistry primer — lipid kinase, not protein kinase PI3Kα transfers ATP γ-phosphate onto PtdIns(4,5)P₂ at the inositol 3-OH. Asp933 deprotonates the hydroxyl; the oxygen attacks γ-P in line, and the γ-phosphate rides across onto the lipid (an associative in-line transfer that inverts the configuration at P — the umbrella flip); ADP leaves. Gold = H⁺. Blue = nucleophile (not hydride). Product is PIP3, a membrane second messenger — not a protein-Ser/Thr phosphate. UniProt P42336 EC = 2.7.1.137 + 2.7.1.153; a reported protein-kinase activity (EC 2.7.11.1, not a UniProt-assigned EC) is named, not shown.
Words used on screen — apo · analog · p85 occupancy · 4JPS Apo — 2RD0 has no nucleotide and no lipid; chemistry uses schematic ATP + PIP2. Analog — the PIP2 headgroup is a short model occupancy for membrane PtdIns(4,5)P₂. p85 occupancy — p85α is required regulatory occupancy; named, not swung. 4JPS — inhibitor 1LT overlay only, never this mesh. PDB numbering = UniProt P42336 1–1068.

Legend & Fidelity

Mechanism fidelity — measured vs. inferred The measured layer: 2RD0 (3.05 Å) apo p110α/p85α; Lys802 NZ ⋯ Asp805 OD2 = 2.58 Å; His917 NE2 ⋯ Asn920 ND2 = 3.23 Å; His917 NE2 ⋯ Asn920 OD1 = 3.27 Å; Lys776 NZ ⋯ Asp805 OD2 = 3.59 Å. The inferred layer ([schematic]): ATP, PIP2, PIP3, ADP, Mg, transferring H⁺/nucleophile spheres, the γ-phosphate ride (drawn in place, not a measured trajectory), the in-line O3⋯P⋯O3B triad (re-posed schematic) + the trigonal-bipyramidal rig/tick (schematic), product leave, and ③/④ split. Binding order is compiled staging, not a kinetic fit. The protein mesh is static. Overlay lipid contacts are not geomClaims. Asp933 is compiled, not UniProt ACT_SITE.
Disagreements on record (a) Apo ≠ ATP ≠ PIP2. 2RD0 has no nucleotide. (b) PIP2 analog ≠ membrane lipid. Headgroup occupancy. (c) Asp933 is compiled. UniProt P42336 has no ACT_SITE for the lipid 3-OH. (d) Concerted vs split. Compiled kinase writes deprotonation + γ-PO₃ transfer as one event; this page splits them (③ then ④). (e) PIK3CB / PIK3CG / PIK3CD are other genes. (f) 4JPS 1LT / 3HHM wortmannin are not this mesh. (g) His1047 is oncogenic, named, not this nucleophile. (h) Protein-kinase EC named, not shown. (i) No protein-domain swing — p85 does not morph.
Regulation — Ras·GTP · p85 · His1047 · isoforms Ras·GTP recruits p110α to membrane PIP2 (HRAS page). p85α is the regulatory subunit — named occupancy, not a swing. His1047 (H1047R) is a common oncogenic mutation — Regulation, not motion. PIK3CB / PIK3CG / PIK3CD are other genes. PTEN removes the 3-phosphate on another page.Source: UniProt P42336 · Huang 2007 PMID:18079394
Kinetics scope (no measured timecourse on this page) One PIP2 + ATP → PIP3 + ADP event is drawn, not a steady-state run. Compiled BRENDA values for EC 2.7.1.153 are not re-asserted here — no measured k_cat/K_m on this page [schematic]. Pair with a kinetics chapter.Source: BRENDA EC 2.7.1.153 — no k_cat/K_m re-asserted
Sequence Human PI3Kα p110α UniProt P42336 · NCBI Gene 5290. Screen uses 2RD0 PDB-author numbering = UniProt 1–1068. p85α fragment is UniProt P27986 442–600 (CA offset +2000).
Simulation map — what you see is what is written Setup = 2RD0 apo cleft empty (opaque, no autoplay); p85 stays. ① PIP2 analog moves in (schematic). ② schematic ATP+Mg move in. ③ gold H⁺ + gold arrow O3 → Asp933 OD2 (parks). ④ slow-mo: blue arrow O3 → γ-P, the γ-phosphate rides off ATP onto the inositol O3 (it travels across the window, not a jump) and the equatorial rig tick sweeps 180° (umbrella inversion); then PIP2+ATP fade to PIP3+ADP; parked gold H⁺ remains. ⑤ products leave opposite ways; p85 stays. Only these events move.
Sources — bibliography of this page S1 — PDB 2RD0: human p110α/p85α apo, 3.05 Å — public coordinates; measured NZ⋯OD2 = 2.58 Å · NE2⋯ND2 = 3.23 Å · NE2⋯OD1 = 3.27 Å · NZ⋯OD2 = 3.59 Å S2 — Huang et al., Science 2007, PMID:18079394 — structure of a human p110α/p85α complex S3 — Sequence: UniProt P42336 (human PIK3CA) · NCBI Gene 5290 S4 — Kinetics: BRENDA EC 2.7.1.153 — no k_cat/K_m re-asserted on this page

› Backbones and ligand poses are taken directly from the listed PDB entries, superposed into one common frame. Where no crystalline state exists for a step (e.g., ATP identity, PIP2 analog, PIP3, ADP after γ-transfer, H⁺ flight, product release), the pose is drawn schematically and labeled as such in the narration.

p110αp85αONH⁺ (gold)nucleophile (blue)