// Fragment-based drug discovery — chaperone · Protein pipeline, Phase 6 evidence layer

HSP90AA1 (heat shock protein 90-alpha)

732 aa (P07900) · predicted structure regenerated live for this page (AlphaFold DB + ANM ensemble + fpocket + cross-frame ranker, same pipeline as every worked example on this site).

// Independently verified against a real PDB structure — not pipeline output

Independently checked against PDB 1YET (HSP90 N-domain + geldanamycin). The correct pocket is present and matches 18 of 19 real contact residues — 95% — including the well-characterized Asn51 and Phe138 contacts, but at rank 2, not rank 1. Rank 1 is a different, non-matching cavity. Structural check: naive whole-domain CA RMSD vs. 1YET is a poor 12.8 Å, almost entirely driven by two regions — residues 11-27 and the well-documented N-domain "lid" (roughly 109-124) — that move by tens of Å; excluding those, the core domain matches at 0.70 Å, near-experimental. HSP90’s N-domain lid is known to close substantially on ligand binding, and the AlphaFold model isn’t in that closed state — real induced-fit flexibility, plausibly the same reason the correct pocket doesn’t rank first, not a modeling failure.

Rank 1 Rank 2 Rank 3

// Sequence

MPEETQTQDQPMEEEEVETFAFQAEIAQLMSLIINTFYSNKEIFLRELISNSSDALDKIRYESLTDPSKLDSGKELHINLIPNKQDRTLTIVDTGIGMTKADLINNLGTIAKSGTKAFMEALQAGADISMIGQFGVGFYSAYLVAEKVTVITKHNDDEQYAWESSAGGSFTVRTDTGEPMGRGTKVILHLKEDQTEYLEERRIKEIVKKHSQFIGYPITLFVEKERDKEVSDDEAEEKEDKEEEKEKEEKESEDKPEIEDVGSDEEEEKKDGDKKKKKKIKEKYIDQEELNKTKPIWTRNPDDITNEEYGEFYKSLTNDWEDHLAVKHFSVEGQLEFRALLFVPRRAPFDLFENRKKKNNIKLYVRRVFIMDNCEELIPEYLNFIRGVVDSEDLPLNISREMLQQSKILKVIRKNLVKKCLELFTELAEDKENYKKFYEQFSKNIKLGIHEDSQNRKKLSELLRYYTSASGDEMVSLKDYCTRMKENQKHIYYITGETKDQVANSAFVERLRKHGLEVIYMIEPIDEYCVQQLKEFEGKTLVSVTKEGLELPEDEEEKKKQEEKKTKFENLCKIMKDILEKKVEKVVVSNRLVTSPCCIVTSTYGWTANMERIMKAQALRDNSTMGYMAAKKHLEINPDHSIIETLRQKAEADKNDKSVKDLVILLYETALLSSGFSLEDPQTHANRIYRMIKLGLGIDEDDPTADDTSAAVTEEMPPLEGDDDTSRMEEVD
Length732 aa
UniProtP07900
Mean structure confidence0.8522
Pocket clusters3

// Confidence flags — rules-based, no learned calibration

infoNo literature-numbering cross-walk available for this target (status=error) — residue numbers in this report are pipeline-sequential only and have NOT been checked against any published numbering convention (e.g. Ambler, Kabat). Do not quote these residue numbers as literature-equivalent without independent verification.

// Findings

Family, precedent, and provenance

Family classification

returned data

HSP90 (PF00183) — Hsp90 protein

E=3.60e-239 · bit score 795.7 · passes GA threshold: yes

Known ligand precedent

returned data

77 total structures in family · 8 distinct ligand scaffolds curated

  • 7U8V — UJS
  • 7U8X — UJV
  • 7U8W — KUC
  • 4IVG — ANP
  • 5TVX — ADP

Conservation

returned data

82 seed sequences · mean pairwise identity 61.4%

Similar known proteins

returned data
  • 7KRJ — 100.0% identity · ATP, DEX
  • 9KQN — 100.0% identity · ADP
  • 9KMR — 100.0% identity · ADP
  • 7L7I — 100.0% identity · ANP
  • 7L7J — 100.0% identity · ANP

Structure-based (Foldseek)

  • 7KRJ — TM 0.992 · 92% id
  • 8EOB — TM 0.991 · 82% id
  • 8EOA — TM 0.988 · 83% id (new vs. sequence list)
  • 8QMO — TM 0.987 · 82% id
  • 8H77 — TM 0.984 · 84% id

Interaction fingerprints (Evidence Integration Layer)

returned data

Representative complex: 7KRJ (ATP, 2.56 Å)

Residue (PDB)Residue (pipeline)InteractionPartner
113113hydrogen bondSER113 (hydrogen bond) with ligand ATP
136136hydrogen bondVAL136 (hydrogen bond) with ligand ATP
137137hydrogen bondGLY137 (hydrogen bond) with ligand ATP
133133hydrogen bondGLN133 (hydrogen bond) with ligand ATP
134134hydrogen bondPHE134 (hydrogen bond) with ligand ATP
113113hydrogen bondSER113 (hydrogen bond) with ligand ATP
135135hydrogen bondGLY135 (hydrogen bond) with ligand ATP
138138hydrogen bondPHE138 (hydrogen bond) with ligand ATP
5151hydrogen bondASN51 (hydrogen bond) with ligand ATP
114114hydrogen bondGLY114 (hydrogen bond) with ligand ATP
115115hydrogen bondTHR115 (hydrogen bond) with ligand ATP
5858hydrogen bondLYS58 (hydrogen bond) with ligand ATP
184184hydrogen bondTHR184 (hydrogen bond) with ligand ATP
400400salt bridgeARG400 (salt bridge) with ligand ATP
9393hydrogen bondASP93 (hydrogen bond) with ligand ATP
113113hydrogen bondSER113 (hydrogen bond) with ligand ATP
136136hydrogen bondVAL136 (hydrogen bond) with ligand ATP
134134hydrogen bondPHE134 (hydrogen bond) with ligand ATP
113113hydrogen bondSER113 (hydrogen bond) with ligand ATP
135135hydrogen bondGLY135 (hydrogen bond) with ligand ATP
137137hydrogen bondGLY137 (hydrogen bond) with ligand ATP
138138hydrogen bondPHE138 (hydrogen bond) with ligand ATP
5151hydrogen bondASN51 (hydrogen bond) with ligand ATP
114114hydrogen bondGLY114 (hydrogen bond) with ligand ATP
115115hydrogen bondTHR115 (hydrogen bond) with ligand ATP
5858hydrogen bondLYS58 (hydrogen bond) with ligand ATP
400400salt bridgeARG400 (salt bridge) with ligand ATP

Representative complex: 9W5I (ATP, 2.63 Å)

Residue (PDB)Residue (pipeline)InteractionPartner
110115hydrogen bondTHR110 (hydrogen bond) with ligand ATP
8893hydrogen bondASP88 (hydrogen bond) with ligand ATP
128133hydrogen bondGLN128 (hydrogen bond) with ligand ATP
129134hydrogen bondPHE129 (hydrogen bond) with ligand ATP
130135hydrogen bondGLY130 (hydrogen bond) with ligand ATP
131136hydrogen bondVAL131 (hydrogen bond) with ligand ATP
132137hydrogen bondGLY132 (hydrogen bond) with ligand ATP
108113hydrogen bondSER108 (hydrogen bond) with ligand ATP
133138hydrogen bondPHE133 (hydrogen bond) with ligand ATP
109114hydrogen bondGLY109 (hydrogen bond) with ligand ATP
110115hydrogen bondTHR110 (hydrogen bond) with ligand ATP
110115hydrogen bondTHR110 (hydrogen bond) with ligand ATP
5358hydrogen bondLYS53 (hydrogen bond) with ligand ATP
392400salt bridgeARG392 (salt bridge) with ligand ATP
110115hydrogen bondTHR110 (hydrogen bond) with ligand ATP
8893hydrogen bondASP88 (hydrogen bond) with ligand ATP
108113hydrogen bondSER108 (hydrogen bond) with ligand ATP
132137hydrogen bondGLY132 (hydrogen bond) with ligand ATP
128133hydrogen bondGLN128 (hydrogen bond) with ligand ATP
129134hydrogen bondPHE129 (hydrogen bond) with ligand ATP
130135hydrogen bondGLY130 (hydrogen bond) with ligand ATP
131136hydrogen bondVAL131 (hydrogen bond) with ligand ATP
133138hydrogen bondPHE133 (hydrogen bond) with ligand ATP
109114hydrogen bondGLY109 (hydrogen bond) with ligand ATP
110115hydrogen bondTHR110 (hydrogen bond) with ligand ATP
110115hydrogen bondTHR110 (hydrogen bond) with ligand ATP
5358hydrogen bondLYS53 (hydrogen bond) with ligand ATP
4651hydrogen bondASN46 (hydrogen bond) with ligand ATP
179184hydrogen bondTHR179 (hydrogen bond) with ligand ATP
392400salt bridgeARG392 (salt bridge) with ligand ATP

Representative complex: 6XLG (AGS, 2.71 Å)

Residue (PDB)Residue (pipeline)InteractionPartner
101115hydrogen bondTHR101 (hydrogen bond) with ligand AGS
7993hydrogen bondASP79 (hydrogen bond) with ligand AGS
99113hydrogen bondSER99 (hydrogen bond) with ligand AGS
118132hydrogen bondGLY118 (hydrogen bond) with ligand AGS
123137hydrogen bondGLY123 (hydrogen bond) with ligand AGS
3751hydrogen bondASN37 (hydrogen bond) with ligand AGS
120134hydrogen bondPHE120 (hydrogen bond) with ligand AGS
121135hydrogen bondGLY121 (hydrogen bond) with ligand AGS
124138hydrogen bondPHE124 (hydrogen bond) with ligand AGS
100114hydrogen bondGLY100 (hydrogen bond) with ligand AGS
101115hydrogen bondTHR101 (hydrogen bond) with ligand AGS
4458hydrogen bondLYS44 (hydrogen bond) with ligand AGS
101115hydrogen bondTHR101 (hydrogen bond) with ligand AGS
7993hydrogen bondASP79 (hydrogen bond) with ligand AGS
99113hydrogen bondSER99 (hydrogen bond) with ligand AGS
118132hydrogen bondGLY118 (hydrogen bond) with ligand AGS
123137hydrogen bondGLY123 (hydrogen bond) with ligand AGS
3751hydrogen bondASN37 (hydrogen bond) with ligand AGS
120134hydrogen bondPHE120 (hydrogen bond) with ligand AGS
121135hydrogen bondGLY121 (hydrogen bond) with ligand AGS
124138hydrogen bondPHE124 (hydrogen bond) with ligand AGS
100114hydrogen bondGLY100 (hydrogen bond) with ligand AGS
101115hydrogen bondTHR101 (hydrogen bond) with ligand AGS
4458hydrogen bondLYS44 (hydrogen bond) with ligand AGS

Structural analysis — ranked pocket clusters

returned data
RankPersistenceResidues
#1153, 57, 60, 126, 127, 128, 129, 131, 214, 215, 216, 295, 297, 298, 299, 300, 301, 328, 329, 330 …
#2138, 47, 48, 51, 52, 54, 55, 58, 93, 96, 97, 98, 106, 107, 112, 113, 114, 115, 132, 134 …
#31494, 495, 496, 497, 501, 502, 505, 507, 545, 599, 601, 607, 608, 609, 612, 672, 673, 674, 675, 676 …

Pocket residues overlapping known interaction sites

  • Pocket 1: no overlap with known interaction sites (29 checked)
  • Pocket 2: residues 51, 58, 93, 113, 114, 115, 132, 134, 135, 136, 137, 138, 184, 400 (14 of 30 pocket residues match a known interaction site)
  • Pocket 3: no overlap with known interaction sites (21 checked)

Pocket functional context (UniProt + ClinVar)

Pocket 1

  • Residue 53: Region — Interaction with NR3C1
  • Residue 57: Region — Interaction with NR3C1
  • Residue 60: Region — Interaction with NR3C1
  • Residue 126: Region — Interaction with NR3C1
  • Residue 127: Region — Interaction with NR3C1
  • Residue 128: Region — Interaction with NR3C1
  • Residue 129: Region — Interaction with NR3C1
  • Residue 131: Region — Interaction with NR3C1
  • Residue 214: Region — Interaction with NR3C1
  • Residue 215: Region — Interaction with NR3C1
  • Residue 216: Region — Interaction with NR3C1
  • Residue 295: Region — Interaction with NR3C1
  • Residue 295: Region — Interaction with FLCN and FNIP1
  • Residue 295: Region — Interaction with FNIP2 and TSC1
  • Residue 297: Region — Interaction with NR3C1
  • Residue 297: Region — Interaction with FLCN and FNIP1
  • Residue 297: Region — Interaction with FNIP2 and TSC1
  • Residue 298: Region — Interaction with NR3C1
  • Residue 298: Region — Interaction with FLCN and FNIP1
  • Residue 298: Region — Interaction with FNIP2 and TSC1
  • Residue 299: Region — Interaction with NR3C1
  • Residue 299: Region — Interaction with FLCN and FNIP1
  • Residue 299: Region — Interaction with FNIP2 and TSC1
  • Residue 300: Region — Interaction with NR3C1
  • Residue 300: Region — Interaction with FLCN and FNIP1
  • Residue 300: Region — Interaction with FNIP2 and TSC1
  • Residue 301: Region — Interaction with NR3C1
  • Residue 301: Region — Interaction with FLCN and FNIP1
  • Residue 301: Region — Interaction with FNIP2 and TSC1
  • Residue 328: Region — Interaction with NR3C1
  • Residue 328: Region — Interaction with FLCN and FNIP1
  • Residue 328: Region — Interaction with FNIP2 and TSC1
  • Residue 329: Region — Interaction with NR3C1
  • Residue 329: Region — Interaction with FLCN and FNIP1
  • Residue 329: Region — Interaction with FNIP2 and TSC1
  • Residue 330: Region — Interaction with NR3C1
  • Residue 330: Region — Interaction with FLCN and FNIP1
  • Residue 330: Region — Interaction with FNIP2 and TSC1
  • Residue 331: Region — Interaction with NR3C1
  • Residue 331: Region — Interaction with FLCN and FNIP1
  • Residue 331: Region — Interaction with FNIP2 and TSC1
  • Residue 332: Region — Interaction with NR3C1
  • Residue 332: Region — Interaction with FLCN and FNIP1
  • Residue 332: Region — Interaction with FNIP2 and TSC1
  • Residue 336: Region — Interaction with NR3C1
  • Residue 336: Region — Interaction with FLCN and FNIP1
  • Residue 336: Region — Interaction with FNIP2 and TSC1
  • Residue 337: Region — Interaction with NR3C1
  • Residue 337: Region — Interaction with FLCN and FNIP1
  • Residue 337: Region — Interaction with FNIP2 and TSC1
  • Residue 338: Region — Interaction with NR3C1
  • Residue 338: Region — Interaction with FLCN and FNIP1
  • Residue 338: Region — Interaction with FNIP2 and TSC1
  • Residue 366: Region — Interaction with NR3C1
  • Residue 366: Region — Interaction with FLCN and FNIP1
  • Residue 366: Region — Interaction with FNIP2 and TSC1
  • Residue 367: Region — Interaction with NR3C1
  • Residue 367: Region — Interaction with FLCN and FNIP1
  • Residue 367: Region — Interaction with FNIP2 and TSC1
  • Residue 390: Region — Interaction with NR3C1
  • Residue 390: Region — Interaction with FLCN and FNIP1
  • Residue 390: Region — Interaction with FNIP2 and TSC1
  • Residue 392: Region — Interaction with NR3C1
  • Residue 392: Region — Interaction with FLCN and FNIP1
  • Residue 392: Region — Interaction with FNIP2 and TSC1

Pocket 2

  • Residue 38: Region — Interaction with NR3C1
  • Residue 47: Region — Interaction with NR3C1
  • Residue 48: Region — Interaction with NR3C1
  • Residue 51: Region — Interaction with NR3C1
  • Residue 51: Binding site — Binding site
  • Residue 52: Region — Interaction with NR3C1
  • Residue 54: Region — Interaction with NR3C1
  • Residue 55: Region — Interaction with NR3C1
  • Residue 58: Region — Interaction with NR3C1
  • Residue 58: Modified residue — N6-acetyllysine
  • Residue 93: Region — Interaction with NR3C1
  • Residue 93: Binding site — Binding site
  • Residue 96: Region — Interaction with NR3C1
  • Residue 97: Region — Interaction with NR3C1
  • Residue 98: Region — Interaction with NR3C1
  • Residue 106: Region — Interaction with NR3C1
  • Residue 107: Region — Interaction with NR3C1
  • Residue 112: Region — Interaction with NR3C1
  • Residue 112: Binding site — Binding site
  • Residue 113: Region — Interaction with NR3C1
  • Residue 114: Region — Interaction with NR3C1
  • Residue 115: Region — Interaction with NR3C1
  • Residue 132: Region — Interaction with NR3C1
  • Residue 134: Region — Interaction with NR3C1
  • Residue 135: Region — Interaction with NR3C1
  • Residue 136: Region — Interaction with NR3C1
  • Residue 137: Region — Interaction with NR3C1
  • Residue 138: Region — Interaction with NR3C1
  • Residue 138: Binding site — Binding site
  • Residue 139: Region — Interaction with NR3C1
  • Residue 150: Region — Interaction with NR3C1
  • Residue 184: Region — Interaction with NR3C1
  • Residue 186: Region — Interaction with NR3C1
  • Residue 398: Region — Interaction with NR3C1
  • Residue 398: Region — Interaction with FLCN and FNIP1
  • Residue 398: Region — Interaction with FNIP2 and TSC1
  • Residue 400: Region — Interaction with NR3C1
  • Residue 400: Region — Interaction with FLCN and FNIP1
  • Residue 400: Region — Interaction with FNIP2 and TSC1
  • Residue 400: Binding site — Binding site

Pocket 3

  • Residue 494: Region — Interaction with NR3C1
  • Residue 494: Region — Interaction with FLCN and FNIP1
  • Residue 494: Region — Interaction with FNIP2 and TSC1
  • Residue 495: Region — Interaction with NR3C1
  • Residue 495: Region — Interaction with FLCN and FNIP1
  • Residue 495: Region — Interaction with FNIP2 and TSC1
  • Residue 496: Region — Interaction with NR3C1
  • Residue 496: Region — Interaction with FLCN and FNIP1
  • Residue 496: Region — Interaction with FNIP2 and TSC1
  • Residue 497: Region — Interaction with NR3C1
  • Residue 497: Region — Interaction with FLCN and FNIP1
  • Residue 497: Region — Interaction with FNIP2 and TSC1
  • Residue 501: Region — Interaction with NR3C1
  • Residue 501: Region — Interaction with FLCN and FNIP1
  • Residue 501: Region — Interaction with FNIP2 and TSC1
  • Residue 502: Region — Interaction with NR3C1
  • Residue 502: Region — Interaction with FLCN and FNIP1
  • Residue 502: Region — Interaction with FNIP2 and TSC1
  • Residue 505: Region — Interaction with NR3C1
  • Residue 505: Region — Interaction with FLCN and FNIP1
  • Residue 505: Region — Interaction with FNIP2 and TSC1
  • Residue 507: Region — Interaction with NR3C1
  • Residue 507: Region — Interaction with FLCN and FNIP1
  • Residue 507: Region — Interaction with FNIP2 and TSC1
  • Residue 545: Region — Interaction with NR3C1
  • Residue 545: Region — Interaction with FLCN and FNIP1
  • Residue 545: Region — Interaction with FNIP2 and TSC1
  • Residue 599: Region — Interaction with NR3C1
  • Residue 599: Region — Interaction with FLCN and FNIP1
  • Residue 599: Region — Interaction with FNIP2 and TSC1
  • Residue 601: Region — Interaction with NR3C1
  • Residue 601: Region — Interaction with FLCN and FNIP1
  • Residue 601: Region — Interaction with FNIP2 and TSC1
  • Residue 607: Region — Interaction with NR3C1
  • Residue 607: Region — Interaction with FLCN and FNIP1
  • Residue 607: Region — Interaction with FNIP2 and TSC1
  • Residue 608: Region — Interaction with NR3C1
  • Residue 608: Region — Interaction with FLCN and FNIP1
  • Residue 608: Region — Interaction with FNIP2 and TSC1
  • Residue 609: Region — Interaction with NR3C1
  • Residue 609: Region — Interaction with FLCN and FNIP1
  • Residue 609: Region — Interaction with FNIP2 and TSC1
  • Residue 612: Region — Interaction with NR3C1
  • Residue 612: Region — Interaction with FLCN and FNIP1
  • Residue 612: Region — Interaction with FNIP2 and TSC1
  • Residue 672: Region — Interaction with FLCN and FNIP1
  • Residue 672: Region — Interaction with NR1D1
  • Residue 673: Region — Interaction with FLCN and FNIP1
  • Residue 673: Region — Interaction with NR1D1
  • Residue 674: Region — Interaction with FLCN and FNIP1
  • Residue 674: Region — Interaction with NR1D1
  • Residue 675: Region — Interaction with FLCN and FNIP1
  • Residue 675: Region — Interaction with NR1D1
  • Residue 676: Region — Interaction with FLCN and FNIP1
  • Residue 676: Region — Interaction with NR1D1
  • Residue 677: Region — Interaction with FLCN and FNIP1
  • Residue 677: Region — Interaction with NR1D1

// Limitations & data provenance

Auto-populated from each section’s own status — not hand-maintained.

Family classificationreturned data
Known ligand precedentreturned data
Interaction fingerprintsreturned data
Functional contextreturned data
Conservationreturned data
Structural analysisreturned data
Similar known proteinsreturned data
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