4XIT

Discovery of novel oxazepine and diazepine carboxamides as two new classes of heat shock protein 90 inhibitors

PDB DOI: https://doi.org/10.2210/pdb4XIT/pdb

Classification: Chaperone/chaperone Inhibitor
Organism(s): Homo sapiens
Expression System: Spodoptera frugiperda
Mutation(s): No

Deposited: 2015-01-07 Released: 2015-03-04
Deposition Author(s): Zuccola, H.J., Neubert, T.

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 1.86 Å
R-Value Free: 0.223
R-Value Work: 0.200
R-Value Observed: 0.201

wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

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

Literature

Discovery of novel oxazepine and diazepine carboxamides as two new classes of heat shock protein 90 inhibitors.

Neubert, T., Numa, M., Ernst, J., Clemens, J., Krenitsky, P., Liu, M., Fleck, B., Woody, L., Zuccola, H., Stamos, D.

(2015) Bioorg Med Chem Lett 25: 1338-1342

PubMed: 25677667 Search on PubMed
DOI: https://doi.org/10.1016/j.bmcl.2015.01.023
Primary Citation of Related Structures:
4XIP, 4XIQ, 4XIR, 4XIT

PubMed Abstract:
Two novel series of oxazepine and diazepine based HSP90 inhibitors are reported. This effort relied on structure based design and isothermal calorimetry to identify small drug like macrocycles. Computational modelling was used to build into a solvent exposed pocket near the opening of the ATP binding site, which led to potent inhibitors of HSP90 (25-30).

Organizational Affiliation

Vertex Pharmaceuticals Incorporated, Department of Chemistry, 11010 Torreyana Road, San Diego, CA 92121, United States. Electronic address: timothy_neubert@vrtx.com.

Macromolecule Content

Total Structure Weight: 26.73 kDa
Atom Count: 1,863
Modelled Residue Count: 208
Deposited Residue Count: 233
Unique protein chains: 1

Macromolecules

Find similar proteins by:

(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
Heat shock protein HSP 90-alpha	A	233	Homo sapiens	Mutation(s): 0 Gene Names: HSP90AA1, HSP90A, HSPC1, HSPCA
UniProt & NIH Common Fund Data Resources
Find proteins for P07900 (Homo sapiens) Explore P07900 Go to UniProtKB: P07900
PHAROS: P07900 GTEx: ENSG00000080824
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	P07900
Sequence Annotations Expand
Reference Sequence

Small Molecules

Ligands 2 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
40Z Query on 40Z Download Ideal Coordinates CCD File SDF format, chain B [auth A] MOL2 format, chain B [auth A]	B [auth A]	2-chloro-5-(furan-2-ylmethyl)-8,11,11-trimethyl-9-oxo-6,7,9,10,11,12-hexahydro-5H-indolo[1,2-a][1,5]benzodiazepine-3-carboxamide C₂₅ H₂₆ Cl N₃ O₃ WLYVWBDERITHJM-UHFFFAOYSA-N		Interactions Focus chain B [auth A] Interactions & Density Focus chain B [auth A]
GOL Query on GOL Download Ideal Coordinates CCD File SDF format, chain C [auth A] MOL2 format, chain C [auth A]	C [auth A]	GLYCEROL C₃ H₈ O₃ PEDCQBHIVMGVHV-UHFFFAOYSA-N		Interactions Focus chain C [auth A] Interactions & Density Focus chain C [auth A]

Binding Affinity Annotations
ID	Source	Binding Affinity
40Z	Binding MOAD: 4XIT	Ki: 41 (nM) from 1 assay(s)

Experimental Data & Validation

Experimental Data

Method: X-RAY DIFFRACTION
Resolution: 1.86 Å
R-Value Free: 0.223
R-Value Work: 0.200
R-Value Observed: 0.201
Space Group: I 2 2 2

Unit Cell:

Length ( Å )	Angle ( ˚ )
a = 66.853	α = 90
b = 91.333	β = 90
c = 98.543	γ = 90

Software Package:

Software Name	Purpose
BUSTER	refinement
PROCESS	data reduction
PROCESS	data scaling
BUSTER	phasing

Structure Validation

View Full Validation Report

Ligand Structure Quality Assessment

Entry History

Deposition Data

Released Date: 2015-03-04

Deposition Author(s):

Zuccola, H.J.

Neubert, T.

Revision History (Full details and data files)

Version 1.0: 2015-03-04
Type: Initial release
Version 1.1: 2015-04-01
Changes: Database references
Version 1.2: 2016-06-01
Changes: Data collection
Version 1.3: 2024-02-28
Changes: Data collection, Database references, Derived calculations