PTEN Phosphatase - 3D Mechanism Simulator

Loading structural data… (1D5R)

References & Databases

START HERE — how to read PIP3 + H₂O → PIP2 + Pi A single lipid 3-phosphatase cartoon on the human PTEN frame that exists: 1D5R (2.10 Å), chain A, with tartrate. That tartrate is a named occupancy, not PIP3 and not Pi. The PIP3 analog is [schematic]. PIP2 analog, cysteinyl-P, Pi, and water are [schematic]. Cys124 is the HCX5R nucleophile. Gold H⁺ leaves water; blue is the Cys-SG nucleophile, not a hydride; the 3-phosphate rides off the lipid onto Cys124, and later the OH⁻ rides onto the E~P. Overlay phospho-lipid contacts are not geomClaims. UniProt P60484 lists EC 3.1.3.67 (this lipid 3-phosphatase), 3.1.3.48 (protein-tyrosine phosphatase) and 3.1.3.16 (protein-serine/threonine phosphatase); only the lipid step is drawn. Not a pure A-page (E~P covalent).
Crystal structures PDB 1D5R — human PTEN + tartrate, 2.10 Å (Lee 1999). Coordinates are public. Tartrate is occupancy. Protein-Tyr phosphatase complexes are not this mesh.
Mechanism — Cys124 nucleophile, cysteinyl-P, water hydrolysis Lee et al., Cell 1999, PMID:10555148 — PTEN tumor-suppressor structure. UniProt P60484 HCX5R nucleophile maps to Cys124 on 1D5R. Arg130 orients the phosphate mimic. Product is PtdIns(4,5)P₂, not a protein phosphate. Protein-Tyr phosphatase EC (3.1.3.48 / 3.1.3.16) is named, not shown. Source: Lee 1999 · UniProt P60484
0 — Setup: tartrate occupies the phosphate cleft 1D5R holds PTEN and tartrate. The tartrate is the crystal occupant — not PIP3 and not Pi. Opaque, no autoplay. Chemistry below uses schematic PIP3 analog. Cys124 SG ⋯ TLA O3 = 3.01 Å on this deposit.Source: PDB 1D5R
① — PIP3 analog presented A short PtdIns(3,4,5)P₃ analog docks as a named stand-in for membrane PIP3 — [schematic], not a crystal lipid. The 3-phosphate faces Cys124. Overlay phospho-lipid contacts are not geomClaims. Protein-Tyr phosphatase is named, not this analog.Source: compiled PTEN substrate identity · UniProt P60484
② — Cys124 attacks P → covalent E~P (hypothetical, lit.-based) The Cys124 thiolate (blue) attacks the analog 3-phosphate. In slow motion the 3-phosphate rides off the lipid onto Cys124 SG — it travels across the window, not a teleport — forming the covalent cysteinyl-P (E~P) and releasing the PIP2 analog; the new S–P bond appears as it lands. Through the trigonal-bipyramidal TS the phosphate itself turns over 180° (Sₙ2 inversion) while the purple equatorial rig tick sweeps 180° (umbrella flip). This is a nucleophilic substitution at P, so the phosphate goes onto the enzyme, not onto another substrate. Overlay phospho-lipid contacts are not geomClaims. Not a pure A-page.Source: compiled PTEN HCX5R · UniProt P60484
③ — PIP2 analog leaves (hypothetical, lit.-based) Schematic PIP2 analog departs. E~P stays on Cys124. Teaching = 3-phosphate off the lipid.Source: EC 3.1.3.67 net accounting
④ — Water hydrolyses E~P → Pi (hypothetical, lit.-based) A schematic water sits in line opposite Cys124 S. A gold H⁺ leaves water H2; the remaining OH⁻ then rides onto the E~P phosphorus in slow motion (it travels across the window — not a teleport) and becomes the fourth O of Pi. Only once it bonds does the S–P bond break and the phosphate leave to the Pi site (concerted — the P–S bond does not stretch before the attack). The E~P P passes through a pentacoordinate TBP — the purple equatorial rig tick sweeps 180° (inversion at P). E~P fades to schematic Pi; water is consumed. Overlay hydrolysis contacts are not geomClaims.Source: compiled PTEN hydrolysis · UniProt P60484
⑤ — Pi leaves — 3-phosphate off [schematic] Pi departs. Product is membrane PIP2. Protein-Tyr phosphatase EC is named, not shown. Tartrate was occupancy, not this chemistry.Source: EC 3.1.3.67 net accounting

How to read this page — a first-pass primer First pass: Setup (tartrate seated, Cys124 ★) → ① PIP3 analog docks → ② the 3-phosphate rides onto Cys124 (blue SG → P), analog becomes PIP2 analog + E~P → ③ PIP2 analog leaves → ④ gold H⁺ leaves then the OH⁻ rides onto the E~P → Pi → ⑤ Pi leaves; 3-phosphate off. Second pass: 3.01 / 2.41 / 2.63 / 3.06 Å are crystal facts on 1D5R; PIP3, PIP2, E~P, Pi, water, and H spheres are [schematic]. Third pass: open “Disagreements” for tartrate ≠ PIP3, analog vs membrane lipid, protein-Tyr phosphatase named not shown, and capture vs hydrolysis split.
Chemistry primer — lipid phosphatase, not PTP1B PTEN transfers the PIP3 3-phosphate to a covalent cysteinyl-P (the 3-phosphate rides onto Cys124 SG), then water hydrolyses E~P — the OH⁻ rides onto the E~P phosphorus, so the phosphate ends up as free Pi. Both are associative in-line Sₙ2 at P, so the phosphorus inverts (the purple equatorial rig's tick sweeps 180° — umbrella flip). Gold = H⁺. Blue = Cys-SG nucleophile (not hydride). Product is membrane PIP2 — the reverse of PI3Kα. Protein-Tyr phosphatase EC is named, not shown. This is not PIK3CA adding the 3-phosphate.
Words used on screen — occupancy · analog · E~P · protein-Tyr Occupancy — tartrate is the crystal ligand; never relabeled as PIP3 or Pi. Analog — the PIP3 headgroup is a short model occupancy for membrane PtdIns(3,4,5)P₃. E~P — covalent cysteinyl-P on Cys124. Protein-Tyr — dual-specificity EC named, not this page. PDB numbering = UniProt P60484 (gap 282–312).

Legend & Fidelity

Mechanism fidelity — measured vs. inferred The measured layer: 1D5R (2.10 Å) with tartrate; Cys124 SG ⋯ TLA O3 = 3.01 Å; Asp92 OD2 ⋯ TLA O2 = 2.41 Å; Arg130 NH2 ⋯ TLA O41 = 2.63 Å; Arg130 NE ⋯ TLA O2 = 3.06 Å. The inferred layer ([schematic]): PIP3 analog, PIP2 analog, E~P, Pi, water, transferring H⁺/nucleophile spheres, the 3-phosphate and OH⁻ rides (drawn in place, not measured trajectories), the trigonal-bipyramidal rig/tick (schematic), product leave, and capture/hydrolysis split. Binding order is compiled staging, not a kinetic fit. The protein mesh is static. Overlay phospho-lipid contacts are not geomClaims. Cys124 is 1D5R HCX5R.
Disagreements on record (a) Tartrate ≠ PIP3 ≠ Pi. TLA is occupancy. (b) PIP3 analog ≠ membrane lipid. Headgroup occupancy. (c) EC. UniProt P60484 = 3.1.3.67 (this lipid 3-phosphatase) + 3.1.3.48 (protein-tyrosine phosphatase) + 3.1.3.16 (protein-serine/threonine phosphatase); only the lipid step is drawn. (d) Capture vs hydrolysis split. Compiled PTEN writes two chemical events; this page plays five beats. (e) No protein-domain swing. (f) Not a pure A-page — E~P is covalent. (g) PIK3CA adds this 3-phosphate on another page.
Regulation — PIP3 gate · PIK3CA · C2 · tumor suppressor PIP3 gate — PTEN removes the 3-phosphate that PI3Kα adds. C2 domain associates with membrane — named occupancy, not a swing. Tumor suppressor — loss of PTEN raises PIP3 (Regulation, not motion). Protein-Tyr phosphatase activity is named, not shown.Source: UniProt P60484 · Lee 1999 PMID:10555148
Kinetics scope (no measured timecourse on this page) One PIP3 + H₂O → PIP2 + Pi event is drawn, not a steady-state run. Compiled BRENDA values for EC 3.1.3.67 are not re-asserted here — no measured k_cat/K_m on this page [schematic]. Pair with a kinetics chapter.Source: BRENDA EC 3.1.3.67 — no k_cat/K_m re-asserted
Sequence Human PTEN UniProt P60484 · NCBI Gene 5728. Screen uses 1D5R PDB-author numbering = UniProt (gap 282–312 replaced by Val on this deposit).
Simulation map — what you see is what is written Setup = 1D5R tartrate seated (opaque, no autoplay). ① PIP3 analog moves in (schematic). ② slow-mo: blue SG → P and the 3-phosphate rides off the lipid onto Cys124 (it travels across the window, not a jump); PIP3 fades to PIP2 analog + E~P. ③ PIP2 analog leaves. ④ gold H⁺ leaves, then the OH⁻ rides onto the E~P phosphorus; E~P fades to Pi. ⑤ Pi leaves; 3-phosphate off. Only these events move.
Sources — bibliography of this page S1 — PDB 1D5R: human PTEN·tartrate, 2.10 Å — public coordinates; measured SG⋯O3 = 3.01 Å · OD2⋯O2 = 2.41 Å · NH2⋯O41 = 2.63 Å · NE⋯O2 = 3.06 Å S2 — Lee et al., Cell 1999, PMID:10555148 — crystal structure of the PTEN tumor suppressor S3 — Sequence: UniProt P60484 (human PTEN) · NCBI Gene 5728 S4 — Kinetics: BRENDA EC 3.1.3.67 — 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., PIP3 analog, PIP2 analog, cysteinyl-P, Pi, H⁺ flight, product release), the pose is drawn schematically and labeled as such in the narration.

phosphataseC2ONH⁺ (gold)nucleophile (blue)