Caspase-9 - 3D Mechanism Simulator

Loading structural data… (1JXQ)

References & Databases

START HERE — how to read Asp-Xaa cut on caspase-9 A single initiator-cut cartoon on the CARD-deleted cleaved human caspase-9 frame that exists: 1JXQ (2.80 Å), chain A, with Z-EVD-fmk in the pocket. That motif is a named occupancy — only the Z-cap C1/O1/O2 and the P1-Asp are ordered, so no covalent fmk adduct is modelled — not LEHD and not the cut product. COMPND writes z-VAD-fmk; SEQRES is PHQ-Glu-Val-Asp-CF0 — coordinates win. CF0 and ASP C/O are zero occupancy and are not extracted. The LEHD peptide is [schematic]. N-fragment, C-fragment, thioester, and water are [schematic]. Cys285 (ICE numbering on 1JXQ) is UniProt Cys287. His237 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. CARD is deleted on this mesh. Apoptosome = Regulation, not motion. Caspase-3/7/8 are other genes. Not a pure A-page (E~acyl covalent).
Crystal structures PDB 1JXQ — CARD-deleted cleaved human caspase-9, 2.80 Å (Renatus 2001). Coordinates are public. 1NW9 is the XIAP-bound companion — not this mesh. 2AR9 is the same construct companion. 5JUY is apoptosome CARD occupancy, not the catalytic teaching mesh. Caspase-2/3/7/8/10 structures are other genes.
Mechanism — Cys285 nucleophile, thioester, water hydrolysis Renatus et al., PNAS 2001, PMID:11734640 — dimer formation drives caspase-9 activation. UniProt P55211 nucleophile maps to Cys287 (ICE Cys285 on 1JXQ). His237 is the compiled general base and is present on this map. Product teaching = cleaved Asp-Xaa peptide (LEHD analog). Physiological substrates include procaspase-3 — analog, not this mesh. Source: Renatus 2001 · UniProt P55211
0 — Setup: Z-EVD-fmk occupies the scissile cleft 1JXQ holds CARD-deleted cleaved caspase-9 and Z-EVD-fmk. Only the Z-cap C1/O1/O2 and the P1-Asp are ordered; the fmk warhead (CF0) and the Asp C/O are 0-occupancy, so no covalent adduct is modelled. That motif is the crystal occupant — not LEHD and not the cut product. Opaque, no autoplay. Chemistry below uses schematic LEHD peptide.Source: PDB 1JXQ
① — LEHD analog presented A short LEHD analog docks as a named stand-in for an Asp-Xaa cut — [schematic], not LEHD crystal and not the fmk. Carbonyl faces Cys285. Overlay peptide Å are not geomClaims. CARD is not on this deposit.Source: compiled caspase-9 substrate identity · UniProt P55211
② — Cys285 attacks C → covalent E~acyl (hypothetical, lit.-based) Blue nucleophile rides from Cys285 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 P55211
③ — C-fragment leaves (hypothetical, lit.-based) Schematic C-fragment departs. E~acyl stays on Cys285. Cut teaching = Asp-Xaa opened at one site.Source: EC 3.4.22.62 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 P55211
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 another gene. The fmk was occupancy, not this chemistry. CARD is deleted. Apoptosome is Regulation, not motion.Source: EC 3.4.22.62 net accounting

How to read this page — a first-pass primer First pass: Setup (Z-EVD-fmk seated, Cys285 ★) → ① LEHD 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: 3.99 / 4.00 / 3.22 / 3.18 Å are crystal facts on occupied 1JXQ atoms; peptide, fragments, water, and H spheres are [schematic]. Third pass: open “Disagreements” for fmk ≠ LEHD, COMPND vs SEQRES, ICE vs UniProt numbering, CARD deleted, and apoptosome as Regulation.
Chemistry primer — cysteine protease, initiator not executioner Caspase-9 cuts after Asp via a cysteinyl thioester, then water hydrolyses E~acyl. Gold = H⁺. Blue = Cys-SG nucleophile (not hydride). Teaching substrate = LEHD analog. This is not caspase-3 (executioner, other gene), and not apoptosome assembly.
Words used on screen — occupancy · analog · ICE numbering · CARD Occupancy — Z-EVD-fmk is the crystal ligand (only the Z-cap C1/O1/O2 and the P1-Asp are ordered); never relabeled as LEHD. Analog — the peptide is a short model occupancy for an Asp-Xaa cut. ICE numbering — 1JXQ uses caspase-1 structural numbers; Cys285 on the mesh is UniProt Cys287. CARD deleted — the recruitment domain is not on this catalytic mesh. Apoptosome — Regulation, not motion.

Legend & Fidelity

Mechanism fidelity — measured vs. inferred The measured layer: 1JXQ (2.80 Å) with the ordered Z-EVD-fmk atoms (PHQ C1/O1/O2 + P1-Asp); Cys285 SG ⋯ INH DN = 3.99 Å; Cys285 SG ⋯ INH DCA = 4.00 Å; His237 ND1 ⋯ INH DOD2 = 3.22 Å; Arg179 NH1 ⋯ INH DOD1 = 3.18 Å. The inferred layer ([schematic]): LEHD 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. CF0 and ASP C/O are zero occupancy and are not measured claims.
Disagreements on record (a) Z-EVD-fmk ≠ LEHD ≠ cut product. Occupancy. (b) COMPND writes z-VAD-fmk; SEQRES is PHQ-Glu-Val-Asp-CF0. Coordinates win — EVD, not VAD. (c) Peptide ≠ physiological caspase-9 substrate. LEHD analog is a model occupancy. (d) ICE Cys285 = UniProt Cys287. Screen uses PDB-author (ICE) numbers; UniProt in the drawer. (e) Capture vs hydrolysis split. Compiled cysteine protease writes two chemical events; this page plays five beats. (f) CARD deleted on this mesh. (g) Apoptosome is Regulation, not motion. 5JUY is CARD occupancy, not this catalytic mesh. (h) Caspase-3/7/8 are other genes. (i) No protein-domain swing. (j) Not a pure A-page — E~acyl is covalent. (k) 1NW9 / 2AR9 are not this mesh.
Regulation — apoptosome · dimer · CARD Apoptosome (APAF1·CYCS·CASP9) is named, not animated — 5JUY is CARD occupancy, not this catalytic mesh. Dimerization activates caspase-9 (Renatus 2001) — the dimer partner B is named occupancy, not a morph. CARD is deleted on 1JXQ.Source: UniProt P55211 · Renatus 2001 PMID:11734640
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 3.4.22.62 are not re-asserted here — no measured k_cat/K_m on this page [schematic]. Pair with a kinetics chapter.Source: BRENDA EC 3.4.22.62 — no k_cat/K_m re-asserted
Sequence Human CASP9 UniProt P55211 · NCBI Gene 842. Screen uses 1JXQ ICE numbering. Cys285 ICE = UniProt Cys287. His237 ICE = UniProt His237.
Simulation map — what you see is what is written Setup = 1JXQ Z-EVD-fmk seated (opaque, no autoplay). ① LEHD 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 1JXQ: CARD-deleted cleaved human caspase-9, 2.80 Å — public coordinates; measured occupied SG⋯DN = 3.99 Å · SG⋯DCA = 4.00 Å · ND1⋯DOD2 = 3.22 Å · NH1⋯DOD1 = 3.18 Å S2 — Renatus et al., Proc. Natl. Acad. Sci. U.S.A. 2001, PMID:11734640 — dimer formation drives caspase-9 activation S3 — Sequence: UniProt P55211 (human CASP9) · NCBI Gene 842 S4 — Kinetics: BRENDA EC 3.4.22.62 — 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., LEHD peptide, N/C fragments, thioester, H⁺ flight, product release), the pose is drawn schematically and labeled as such in the narration.

caspase-9dimer partnerONH⁺ (gold)nucleophile (blue)