STRC Research

log

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h26 log

2026-04-23

  • Phase 1c contact re-cluster: GREEN. DBSCAN eps=6.5 Å on Ultra-Mini homodimer CIF found 3 clusters. Cluster 1 “stump” 1077-1114 (25 residues, 21 Cb-Cb disulfide geometries) ENTIRELY outside Phase 1 target 1579-1581. Native C1079+C1081 on both chains sit 6.87-7.09 Å from A1078/S1080 on opposing chain → single A1078C or S1080C engineers inter-chain disulfide without changing cystine count. Cluster 2 ARM has homotypic S1579C/S1579C at Cb-Cb 6.94 Å (re-opens Phase 1 target with disulfide chemistry). B held pending Phase 1d AF3 triple batch (A1078C + S1080C + S1579C homotypic + A1078W negative control). Promotion path: Phase 1d ipTM ≥0.50 + homodimer contacts ≥ WT → A-tier → drop into h03 Ultra-Mini as engineered-avidity variant (zero payload cost). → STRC h26 Phase 1c Contact Re-Cluster 2026-04-23
  • Added to register: A-tier, Mech 4, Deliv 5, Misha 4. R-R repulsion at ARM 1579-1581 identified as dimer destabilizer → STRC Engineered Homodimer Avidity
  • Phase 1 AF3 batch built: 5 jobs (WT + 4 single-point mutants × 2 TMEM145), awaiting submission → STRC Engineered Homodimer Avidity
  • Phase 1 AF3 returned 4 mutants (WT_ref not downloaded): all FAIL homodimer gate (mean 0.15-0.19 vs WT 0.28-0.30); 3/4 also destroy TMEM145 binding → STRC Engineered Homodimer Phase 1 Results
  • Tier A → B. Mech 4→3. R-R repulsion falsified by R1581F (arg removed, homodimer still weak) → STRC Engineered Homodimer Phase 1 Results
  • Dunbrack 2025 ipSAE reassessment: Ultra-Mini homodimer ipSAE 0.000 (zero interface residues pass PAE<10 Å cutoff at default AF3 settings) — ipTM 0.28-0.30 uplift from baseline 0.20-0.24 now identified as disordered-region false-positive pattern ipSAE was designed to catch. Mech 3→2, B held. Structural symmetry (94% C2) + aa 1579-1581 self-contacts legs survive the reassessment (they are geometry observations independent of the confidence metric). Phase 1c 5 Å re-cluster still the next viable move. → STRC ipSAE Cross-Complex Reassessment 2026-04-23

2026-04-23

  • #26 Engineered Homodimer Phase 1c GREEN: spatial DBSCAN (eps 6.5 Å) re-cluster of Ultra-Mini homodimer inter-chain contacts found 3 clusters. Cluster 1 “stump” 1077-1114 (25 residues, 21 disulfide-geometry Cb-Cb in 4.5-7.5 Å window) is entirely outside Phase 1’s tested 1579-1581 target. Native C1081 sits within Cb-Cb 6.87-7.09 Å of A1078/C1079/S1080 on opposing chain — latent inter-chain cystine site. Cluster 2 (ARM 1529-1590) also contains untouched candidates incl. homotypic S1579→C/S1579→C symmetric disulfide at Cb-Cb 6.94 Å (re-opens ARM target with different chemistry than Phase 1’s aromatic Y/F mutants). B held pending Phase 1d AF3 triple batch (A1078C, S1080C, S1579C homotypic mutants + A1078W negative control). Promotion path: Phase 1d ipTM ≥ 0.50 + homodimer contacts ≥ WT → A-tier → drop-in to h03 Ultra-Mini as engineered-avidity variant. → STRC h26 Phase 1c Contact Re-Cluster 2026-04-23
  • #9 Hydrogel + #26 Homodimer: ipSAE (Dunbrack 2025) reassessment on 6 STRC AF3 jobs (incl. 2 known positive + 2 known negative controls). Ultra-Mini × TMEM145 GOLD ipSAE 0.591 sits in known-binder-zone (NFAT-CnB 0.55 … NFAT-CnA 0.78 physiological binders) → h09 gate 3 narrowed from “unsupported placeholder” to “band-consistent 10 nM-10 µM, wet-lab still gating absolute Kd”; A held, Mech 4 held. Ultra-Mini homodimer ipSAE 0.000 (zero interface residues pass PAE<10 Å) contradicts prior ipTM 0.28-0.30 weak-binder interpretation per Dunbrack’s disordered-region-false-positive fix → #26 Mech 3→2, B held. Path B (AF3 absolute Kd calibration) closed as lit-infeasible. → STRC ipSAE Cross-Complex Reassessment 2026-04-23
  • #9 Hydrogel + #26 Homodimer: ipSAE (Dunbrack 2025) reassessment on 6 STRC AF3 jobs (incl. 2 known positive + 2 known negative controls). Ultra-Mini × TMEM145 GOLD ipSAE 0.591 sits in known-binder-zone (NFAT-CnB 0.55 … NFAT-CnA 0.78 physiological binders) → h09 gate 3 narrowed from “unsupported placeholder” to “band-consistent 10 nM-10 µM, wet-lab still gating absolute Kd”; A held, Mech 4 held. Ultra-Mini homodimer ipSAE 0.000 (zero interface residues pass PAE<10 Å) contradicts prior ipTM 0.28-0.30 weak-binder interpretation per Dunbrack’s disordered-region-false-positive fix → #26 Mech 3→2, B held. Path B (AF3 absolute Kd calibration) closed as lit-infeasible. → STRC ipSAE Cross-Complex Reassessment 2026-04-23
  • #26 Engineered Homodimer: A → B. Mech 4→3. Phase 1 AF3 ALL FAIL: single-point mutants destabilize homodimer (mean 0.15-0.19 vs WT 0.28-0.30); R-R repulsion hypothesis falsified. → STRC Engineered Homodimer Phase 1 Results
  • #26 STRC Engineered Homodimer Avidity added, A-tier. Phase 1 AF3 batch built (5 jobs). → STRC Engineered Homodimer Avidity
  • #26 Homodimer Avidity post-audit fix: B held. Prose phantoms reframed: “100 nM → 1 nM” Kd claims now explicit ratio-on-unmeasured-baseline; status banner notes Phase 1 AF3 fail + unmeasured Kd; avidity principle (Jencks 1981, Mammen 1998, Kramer & Karpen 1998) real; absolute Kd claims placeholder. Mech 4→3 (Phase 1 structural fail). → STRC Engineered Homodimer Avidity

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