This page summarizes the 2.14 Å crystal structure of the N-terminal domain of human Heat Shock Protein 90 (Hsp90N) bound to the potent small-molecule inhibitor SNX-2112, as published in:
Complex Crystal Structure Determination and In Vitro Anti–Non-Small Cell Lung Cancer Activity of Hsp90N Inhibitor SNX-2112
[1].
</Structure Section>
Structure
The structure 6LTK reveals the Hsp90N domain in complex with SNX-2112 occupying the ATP-binding pocket.
• Resolution: **2.14 Å (X-ray diffraction)**
• SNX-2112 binds deeply inside the nucleotide-binding cleft
• Key interacting residues: **Asp93, Phe138, Tyr139, Leu107, Met98**
• Stabilization via hydrogen bonds + hydrophobic contacts
• The inhibitor mimics ATP binding but locks Hsp90 in an inactive state
Function
Hsp90 is an ATP-dependent molecular chaperone essential for folding and stabilizing many signaling proteins, including kinases and receptors.
The **N-terminal domain** contains the ATP-binding pocket required for its chaperone cycle.
Binding of SNX-2112 inhibits ATP hydrolysis → halts client protein maturation.
Disease relevance
Hsp90 is overexpressed in several cancers, including **non-small cell lung cancer (NSCLC)**. Tumor cells rely heavily on Hsp90 to stabilize oncogenic proteins such as:
• **AKT**
• **Raf-1**
• **HER2**
• **EGFR**
Thus, targeting Hsp90 causes misfolding and degradation of these client proteins, suppressing cancer cell proliferation.
Relevance
The 6LTK structure provides a template for:
• Structure-guided optimization of SNX-2112 analogs
• Developing next-generation Hsp90 inhibitors with reduced toxicity
• Understanding selectivity for Hsp90N over other chaperones
• Designing NSCLC-specific therapeutic candidates
Structural highlights
• SNX-2112 forms strong H-bonding interactions with **Asp93**, a residue also required for ATP anchoring.
• Hydrophobic residues (Leu107, Met98, Phe138) create a deep pocket that tightly holds SNX-2112.
• The inhibitor induces slight rearrangements in the lid region over the cleft.
• Surface-view analysis shows SNX-2112 completely plugs the ATP pocket.
Images
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3D Scenes (interactive)
Methods / Data Sources
• PDB ID: **6LTK**
• Experimental method: **X-ray crystallography (2.14 Å)**
• Organism: *Homo sapiens* Hsp90N domain
• Ligand: **SNX-2112 (inhibitor)**
• Expression system: Recombinant protein expressed in *E. coli*
References
- ↑ doi: https://dx.doi.org/10.3389/fmolb.2021.670964
PyMOL Scripts
1. Cartoon + ligand highlight
fetch 6ltk, async=0
hide everything
show cartoon, 6ltk
color sky blue, 6ltk
show sticks, organic
color yellow, organic
set cartoon_transparency, 0.2
2. Binding pocket close-up
fetch 6ltk
select pocket, byres organic expand 4
show surface, pocket
set transparency, 0.35
show sticks, organic
orient organic
3. Hydrophobic interactions view
fetch 6ltk
select hydro, resn LEU+MET+PHE+ILE+VAL within 4 of organic
show sticks, hydro
color orange, hydro
show sticks, organic
zoom organic
