6AOM | pdb_00006aom

Structure of molecular chaperone Grp94 bound to selective inhibitor methyl 2-[2-(2-benzylphenyl)ethyl]-3-chloro-4,6-dihydroxybenzoate

PDB DOI: https://doi.org/10.2210/pdb6AOM/pdb

Classification: CHAPERONE/INHIBITOR
Organism(s): Canis lupus familiaris
Expression System: Escherichia coli
Mutation(s): No

Deposited: 2017-08-16 Released: 2017-10-11
Deposition Author(s): Lieberman, R.L., Huard, D.J.E.

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 2.87 Å
R-Value Free:
0.272 (Depositor), 0.270 (DCC)
R-Value Work:
0.200 (Depositor), 0.200 (DCC)
R-Value Observed:
0.207 (Depositor)

Starting Model: experimental
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wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

This is version 1.3 of the entry. See complete history.

Literature

Second Generation Grp94-Selective Inhibitors Provide Opportunities for the Inhibition of Metastatic Cancer.

Crowley, V.M., Huard, D.J.E., Lieberman, R.L., Blagg, B.S.J.

(2017) Chemistry 23: 15775-15782

PubMed: 28857290 Search on PubMedSearch on PubMed Central
DOI: https://doi.org/10.1002/chem.201703398
Primary Citation of Related Structures:
6AOL, 6AOM

PubMed Abstract:
Glucose regulated protein 94 (Grp94) is the endoplasmic reticulum (ER) resident isoform of the 90 kDa heat shock protein (Hsp90) family and its inhibition represents a promising therapeutic target for the treatment of many diseases. Modification of the first generation cis-amide bioisostere imidazole to alter the angle between the resorcinol ring and the benzyl side chain via cis-amide replacements produced compounds with improved Grp94 affinity and selectivity. Structure-activity relationship studies led to the discovery of compound 30, which exhibits 540 nm affinity and 73-fold selectivity towards Grp94. Grp94 is responsible for the maturation and trafficking of proteins associated with cell signaling and motility, including select integrins. The Grp94-selective inhibitor 30 was shown to exhibit potent anti-migratory effects against multiple aggressive and metastatic cancers.

Organizational Affiliation

Department of Medicinal Chemistry, The University of Kansas, 1251 Wescoe Hall Dr. Malott 4070, Lawrence, KS, 66045, USA.

Macromolecule Content

Total Structure Weight: 58.26 kDa
Atom Count: 3,615
Modelled Residue Count: 427
Deposited Residue Count: 466
Unique protein chains: 1

Macromolecules

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(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
Endoplasmin	A, B	233	Canis lupus familiaris	Mutation(s): 0 Gene Names: HSP90B1, GRP94, TRA1
UniProt
Find proteins for P41148 (Canis lupus familiaris) Explore P41148 Go to UniProtKB: P41148
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	P41148
Sequence Annotations Expand
Reference Sequence LOADING

Small Molecules

Ligands 4 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
VC5 Query on VC5 Download Ideal Coordinates CCD File SDF format, chain K [auth A] SDF format, chain U [auth B] MOL2 format, chain K [auth A] MOL2 format, chain U [auth B] mmCIF format, chain K [auth A] mmCIF format, chain U [auth B]	K [auth A], U [auth B]	methyl 2-[2-(2-benzylphenyl)ethyl]-3-chloro-4,6-dihydroxybenzoate C₂₃ H₂₁ Cl O₄ RHHYIPFMHURXDZ-UHFFFAOYSA-N		Interactions Focus chain K [auth A] Focus chain U [auth B] Interactions & Density Focus chain K [auth A] Focus chain U [auth B]
P33 Query on P33 Download Ideal Coordinates CCD File SDF format, chain C [auth A] SDF format, chain D [auth A] SDF format, chain E [auth A] SDF format, chain F [auth A] SDF format, chain G [auth A] SDF format, chain H [auth A] SDF format, chain I [auth A] SDF format, chain J [auth A] SDF format, chain M [auth B] SDF format, chain N [auth B] SDF format, chain O [auth B] SDF format, chain S [auth B] SDF format, chain T [auth B] SDF format, chain Q [auth B] SDF format, chain R [auth B] MOL2 format, chain C [auth A] MOL2 format, chain D [auth A] MOL2 format, chain E [auth A] MOL2 format, chain F [auth A] MOL2 format, chain G [auth A] MOL2 format, chain H [auth A] MOL2 format, chain I [auth A] MOL2 format, chain J [auth A] MOL2 format, chain M [auth B] MOL2 format, chain N [auth B] MOL2 format, chain O [auth B] MOL2 format, chain S [auth B] MOL2 format, chain T [auth B] MOL2 format, chain Q [auth B] MOL2 format, chain R [auth B] mmCIF format, chain C [auth A] mmCIF format, chain D [auth A] mmCIF format, chain E [auth A] mmCIF format, chain F [auth A] mmCIF format, chain G [auth A] mmCIF format, chain H [auth A] mmCIF format, chain I [auth A] mmCIF format, chain J [auth A] mmCIF format, chain M [auth B] mmCIF format, chain N [auth B] mmCIF format, chain O [auth B] mmCIF format, chain S [auth B] mmCIF format, chain T [auth B] mmCIF format, chain Q [auth B] mmCIF format, chain R [auth B]	C [auth A] D [auth A] E [auth A] F [auth A] G [auth A] C [auth A], D [auth A], E [auth A], F [auth A], G [auth A], H [auth A], I [auth A], J [auth A], M [auth B], N [auth B], O [auth B], Q [auth B], R [auth B], S [auth B], T [auth B]	3,6,9,12,15,18-HEXAOXAICOSANE-1,20-DIOL C₁₄ H₃₀ O₈ XPJRQAIZZQMSCM-UHFFFAOYSA-N		Interactions Focus chain C [auth A] Focus chain D [auth A] Focus chain E [auth A] Focus chain F [auth A] Focus chain G [auth A] Focus chain H [auth A] Focus chain I [auth A] Focus chain J [auth A] Focus chain M [auth B] Focus chain N [auth B] Focus chain O [auth B] Focus chain Q [auth B] Focus chain R [auth B] Focus chain S [auth B] Focus chain T [auth B] Interactions & Density Focus chain C [auth A] Focus chain D [auth A] Focus chain E [auth A] Focus chain F [auth A] Focus chain G [auth A] Focus chain H [auth A] Focus chain I [auth A] Focus chain J [auth A] Focus chain M [auth B] Focus chain N [auth B] Focus chain O [auth B] Focus chain Q [auth B] Focus chain R [auth B] Focus chain S [auth B] Focus chain T [auth B]
PEG Query on PEG Download Ideal Coordinates CCD File SDF format, chain P [auth B] MOL2 format, chain P [auth B] mmCIF format, chain P [auth B]	P [auth B]	DI(HYDROXYETHYL)ETHER C₄ H₁₀ O₃ MTHSVFCYNBDYFN-UHFFFAOYSA-N		Interactions Focus chain P [auth B] Interactions & Density Focus chain P [auth B]
GOL Query on GOL Download Ideal Coordinates CCD File SDF format, chain L [auth A] MOL2 format, chain L [auth A] mmCIF format, chain L [auth A]	L [auth A]	GLYCEROL C₃ H₈ O₃ PEDCQBHIVMGVHV-UHFFFAOYSA-N		Interactions Focus chain L [auth A] Interactions & Density Focus chain L [auth A]

Experimental Data & Validation

Experimental Data

Method: X-RAY DIFFRACTION
Resolution: 2.87 Å
R-Value Free: 0.272 (Depositor), 0.270 (DCC)
R-Value Work: 0.200 (Depositor), 0.200 (DCC)
R-Value Observed: 0.207 (Depositor)

Space Group: P 2₁ 2₁ 2₁

Unit Cell:

Length ( Å )	Angle ( ˚ )
a = 65.454	α = 90
b = 84.233	β = 90
c = 94.966	γ = 90

Software Package:

Software Name	Purpose
PHENIX	refinement
HKL-3000	data reduction
HKL-3000	data scaling
PHASER	phasing

Structure Validation

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Ligand Structure Quality Assessment

Entry History

Deposition Data

Released Date: 2017-10-11

Deposition Author(s):

Lieberman, R.L.

Huard, D.J.E.

Revision History (Full details and data files)

Version 1.0: 2017-10-11
Type: Initial release
Version 1.1: 2017-11-22
Changes: Database references
Version 1.2: 2018-01-17
Changes: Author supporting evidence
Version 1.3: 2023-10-04
Changes: Data collection, Database references, Refinement description, Structure summary

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Help and Resources

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Structure of molecular chaperone Grp94 bound to selective inhibitor methyl 2-[2-(2-benzylphenyl)ethyl]-3-chloro-4,6-dihydroxybenzoate

Second Generation Grp94-Selective Inhibitors Provide Opportunities for the Inhibition of Metastatic Cancer.

Entity ID: 1

UniProt

Entity Groups

Sequence Annotations

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