Caspase-8 - 3D Mechanism Simulator

Loading structural data… (1QTN)

References & Databases

START HERE — how to read Asp-Xaa cut on caspase-8 A single extrinsic-initiator-cut cartoon on the cleaved human caspase-8 frame that exists: 1QTN (1.20 Å), chain A, with Ac-IETD-CHO in the pocket. That motif is a named aldehyde occupancy, not IETD substrate and not the cut product. TITLE writes ACE-IETD-ALDEHYDE; SEQRES is ACE-Ile-Glu-Thr-ASJ — coordinates match IETD-CHO. ASJ C is occupied and is extracted (hemithioacetal adduct). The IETD peptide is [schematic]. N-fragment, C-fragment, thioester, and water are [schematic]. Cys360 is UniProt Cys360. His317 is present. Gold H⁺ leaves water; blue is the Cys-SG nucleophile, not a hydride. Overlay peptide distances are not geomClaims. Dimer partner B is named occupancy, not animated. DED domains are not on this catalytic mesh. Death-receptor card is Regulation, not motion. Extrinsic initiator, not executioner. Caspase-3/7/9/10 are other genes. Not a pure A-page (E~acyl covalent).
Crystal structures PDB 1QTN — human caspase-8 + Ac-IETD-CHO, 1.20 Å (Watt 1999). Coordinates are public. DTD is a crystallization additive — not this mesh. Caspase-3/7/9/10 structures are other genes. DED-domain crystals are not this catalytic mesh.
Mechanism — Cys360 nucleophile, thioester, water hydrolysis Watt et al., Structure 1999, PMID:10508785 — atomic-resolution human caspase-8 with acetyl-Ile-Glu-Thr-Asp-aldehyde. UniProt Q14790 nucleophile is Cys360. His317 is the compiled general base and is present on this map. Product teaching = cleaved Asp-Xaa peptide (IETD analog). Physiological substrates include procaspase-3 — analog, not this mesh. Source: Watt 1999 · UniProt Q14790
0 — Setup: Ac-IETD-CHO occupies the scissile cleft 1QTN holds cleaved caspase-8 and Ac-IETD-CHO. That motif is the crystal occupant — not IETD substrate and not the cut product. Opaque, no autoplay. Chemistry below uses schematic IETD peptide.Source: PDB 1QTN
① — IETD analog presented A short IETD analog docks as a named stand-in for an Asp-Xaa cut — [schematic], not IETD crystal and not the aldehyde. Carbonyl faces Cys360. Overlay peptide Å are not geomClaims.Source: compiled caspase-8 substrate identity · UniProt Q14790
② — Cys360 attacks C → covalent E~acyl (hypothetical, lit.-based) Blue nucleophile rides from Cys360 SG to analog C. Intact peptide fades in place to schematic N-fragment + C-fragment; the carbonyl C then slides to a real ~1.8 Å C–S covalent distance (thioester — the E~acyl bond length, no 3.2 Å gap). Overlay peptide Å are not geomClaims. Slow-motion on purpose. Not a pure A-page.Source: compiled caspase Cys · UniProt Q14790
③ — C-fragment leaves (hypothetical, lit.-based) Schematic C-fragment departs. E~acyl stays on Cys360. Cut teaching = Asp-Xaa opened at one site.Source: EC 3.4.22.61 net accounting
④ — Water hydrolyses E~acyl (hypothetical, lit.-based) A schematic water moves in (glides) to the E~acyl face. Gold H⁺ leaves water H2 on the yellow arrow and vanishes right at the arrow tip at the leaving SG (thiol). Remaining O–H = OH⁻ attacks the carbonyl along the blue arrow; after the swap the water O is bound as the new carboxylate O on the N-fragment (red ball) and leaves with it. Thioester is hydrolysed — water-O mass is kept, not deleted. Overlay hydrolysis Å are not geomClaims.Source: compiled cysteine-protease hydrolysis · UniProt Q14790
⑤ — N-fragment leaves — cut [schematic] N-fragment departs carrying its new carboxylate O (from H₂O) — the red water O rides out bound to the product. Product teaching = cleaved Asp-Xaa peptide. Caspase-3 is the executioner, another gene. The aldehyde was occupancy, not this chemistry. DED domains are not on this mesh. Death-receptor card is Regulation, not motion.Source: EC 3.4.22.61 net accounting

How to read this page — a first-pass primer First pass: Setup (Ac-IETD-CHO seated, Cys360 ★) → ① IETD analog docks → ② blue SG → C, peptide becomes N + C fragments → ③ C-fragment leaves → ④ gold H⁺ then OH⁻ attacks E~acyl → ⑤ N-fragment leaves; cut. Second pass: 2.98 / 1.77 / 2.79 / 2.99 Å are crystal facts on occupied 1QTN atoms; peptide, fragments, water, and H spheres are [schematic]. Third pass: open “Disagreements” for CHO ≠ IETD substrate, TITLE vs SEQRES, extrinsic initiator vs executioner, and DED domains not on this mesh.
Chemistry primer — cysteine protease, extrinsic initiator not executioner Caspase-8 cuts after Asp via a cysteinyl thioester, then water hydrolyses E~acyl. Gold = H⁺. Blue = Cys-SG nucleophile (not hydride). Teaching substrate = IETD analog. This is not caspase-3 (executioner, other gene), and not a death-receptor assembly movie.
Words used on screen — occupancy · analog · CHO · DED Occupancy — Ac-IETD-CHO is the crystal ligand; never relabeled as IETD substrate. Analog — the peptide is a short model occupancy for an Asp-Xaa cut. CHO — aldehyde hemithioacetal adduct (ASJ C occupied on 1QTN). DED — death-effector domains are not on this catalytic mesh. Death-receptor card — Regulation, not motion.

Legend & Fidelity

Mechanism fidelity — measured vs. inferred The measured layer: 1QTN (1.20 Å) with occupied Ac-IETD-CHO atoms; Cys360 SG ⋯ INH DN = 2.98 Å; Cys360 SG ⋯ INH DC = 1.77 Å; Arg260 NH2 ⋯ INH DOD2 = 2.79 Å; Arg413 NH2 ⋯ INH DOD1 = 2.99 Å. The inferred layer ([schematic]): IETD peptide, N/C fragments, E~acyl, water, transferring H⁺/nucleophile spheres, product leave, and capture/hydrolysis split. Binding order is compiled staging, not a kinetic fit. The protein mesh is static. Overlay peptide contacts are not geomClaims. ASJ C is occupied (hemithioacetal) and is a measured covalent-adduct claim.
Disagreements on record (a) Ac-IETD-CHO ≠ IETD substrate ≠ cut product. Occupancy. (b) TITLE writes ACE-IETD-ALDEHYDE; SEQRES is ACE-Ile-Glu-Thr-ASJ. Coordinates match IETD-CHO. (c) Peptide ≠ physiological caspase-8 substrate. IETD analog is a model occupancy. (d) Cys360 = UniProt Cys360. Screen uses PDB-author numbers that match UniProt here. (e) Capture vs hydrolysis split. Compiled cysteine protease writes two chemical events; this page plays five beats. (f) Extrinsic initiator, not executioner. Caspase-3 is another gene. (g) DED domains are not on this catalytic mesh. (h) Death-receptor card is Regulation, not motion. (i) No protein-domain swing. (j) Not a pure A-page — E~acyl is covalent. (k) DTD is a crystallization additive, not this mesh. (l) ASJ C occupied — hemithioacetal adduct, named occupancy, not the teaching peptide.
Regulation — dimer · death receptor · DISC Dimerization of the p18/p11 heterodimer is the active form on 1QTN — the dimer partner B is named occupancy, not a morph. Activation is by death-receptor DISC (FADD), named, not animated. DED domains are not on this catalytic mesh.Source: UniProt Q14790 · Watt 1999 PMID:10508785
Kinetics scope (no measured timecourse on this page) One Asp-Xaa cleavage event is drawn, not a steady-state run. Compiled BRENDA values for EC 3.4.22.61 are not re-asserted here — no measured k_cat/K_m on this page [schematic]. Pair with a kinetics chapter.Source: BRENDA EC 3.4.22.61 — no k_cat/K_m re-asserted
Sequence Human CASP8 UniProt Q14790 · NCBI Gene 841. Screen uses 1QTN numbering. Cys360 = UniProt Cys360. His317 = UniProt His317.
Simulation map — what you see is what is written Setup = 1QTN Ac-IETD-CHO seated (opaque, no autoplay). ① IETD analog moves in (schematic). ② slow-mo: blue nucleophile SG → C; peptide fades to N + C fragments. ③ C-fragment leaves. ④ gold H⁺ then OH⁻ attacks E~acyl. ⑤ N-fragment leaves; cut. Only these events move.
Sources — bibliography of this page S1 — PDB 1QTN: human caspase-8 + Ac-IETD-CHO, 1.20 Å — public coordinates; measured occupied SG⋯DN = 2.98 Å · SG⋯DC = 1.77 Å · Arg260 NH2⋯DOD2 = 2.79 Å · Arg413 NH2⋯DOD1 = 2.99 Å S2 — Watt et al., Structure 1999, PMID:10508785 — atomic-resolution caspase-8 with Ac-IETD-CHO S3 — Sequence: UniProt Q14790 (human CASP8) · NCBI Gene 841 S4 — Kinetics: BRENDA EC 3.4.22.61 — 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., IETD peptide, N/C fragments, thioester, H⁺ flight, product release), the pose is drawn schematically and labeled as such in the narration.

caspase-8dimer partnerONH⁺ (gold)nucleophile (blue)