Sandbox Anshika Page

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

You can upload PNG images and insert them like this:

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

1. ↑ 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