3R92

Discovery of a macrocyclic o-aminobenzamide Hsp90 inhibitor with heterocyclic tether that shows extended biomarker activity and in vivo efficacy in a mouse xenograft model.

X-RAY DIFFRACTION

Crystallization

Crystalization Experiments
ID	Method	pH	Temperature	Details
1	VAPOR DIFFUSION, HANGING DROP	6.5	277	25% PEG3000, 0.1 M MES, pH 6.5, TEMPERATURE 277K; FROZEN BY 1-STEP TRANSFER TO 25% GLYCEROL, 19% PEG3000, 0.075M MES, VAPOR DIFFUSION, HANGING DROP

Crystal Properties
Matthews coefficient	Solvent content
2.95	58.32

Crystal Data

Unit Cell
Length ( Å )	Angle ( ˚ )
a = 67.35	α = 90
b = 90.355	β = 90
c = 98.594	γ = 90

Symmetry
Space Group	I 2 2 2

Diffraction

Diffraction Experiment
ID #	Crystal ID	Scattering Type	Data Collection Temperature	Detector	Detector Type	Details	Collection Date	Monochromator	Protocol
1	1	x-ray	93	CCD	RIGAKU SATURN 92	mirros	2008-05-30	M	SINGLE WAVELENGTH

Radiation Source
ID #	Source	Type	Wavelength List	Synchrotron Site	Beamline
1	ROTATING ANODE	RIGAKU FR-E+ SUPERBRIGHT	1.5418

Data Collection

Overall
ID #	Resolution (High)	Resolution (Low)	Percent Possible (Observed)	R Sym I (Observed)	Net I Over Average Sigma (I)	Redundancy	Number Reflections (All)	Number Reflections (Observed)	Observed Criterion Sigma (F)	Observed Criterion Sigma (I)	B (Isotropic) From Wilson Plot
1	1.58	24.721	84.87	0.045	25.9	6.6	41549	35263			17.638

Highest Resolution Shell
ID #	Resolution (High)	Resolution (Low)	Percent Possible (All)	Percent Possible (Observed)	R-Sym I (Observed)	Mean I Over Sigma (Observed)	Redundancy	Number Unique Reflections (All)
1	1.58	1.62	53.8		0.501	1.12	1.3	2676

Refinement

Statistics
Diffraction ID	Structure Solution Method	Resolution (High)	Resolution (Low)	Cut-off Sigma (F)	Number Reflections (All)	Number Reflections (Observed)	Number Reflections (R-Free)	Percent Reflections (Observed)	R-Factor (Observed)	R-Work	R-Free	R-Free Selection Details	Mean Isotropic B
X-RAY DIFFRACTION	MOLECULAR REPLACEMENT	1.5801	24.721	0.01	41549	35263	1805	84.87	0.1771	0.1762	0.1938	Random

Temperature Factor Modeling
Anisotropic B[1][1]	Anisotropic B[1][2]	Anisotropic B[1][3]	Anisotropic B[2][2]	Anisotropic B[2][3]	Anisotropic B[3][3]
0.7436			0.8489		-1.7393

RMS Deviations
Key	Refinement Restraint Deviation
f_dihedral_angle_d	13.253
f_angle_d	0.789
f_chiral_restr	0.057
f_bond_d	0.003
f_plane_restr	0.002

Non-Hydrogen Atoms Used in Refinement
Non-Hydrogen Atoms	Number
Protein Atoms	1635
Nucleic Acid Atoms
Solvent Atoms	342
Heterogen Atoms	32

Software

Software
Software Name	Purpose
StructureStudio	data collection
PHASER	phasing
PHENIX	refinement
HKL-2000	data reduction
HKL-2000	data scaling

RCSB PDB Core Operations are funded by the National Science Foundation (DBI-1832184), the US Department of Energy (DE-SC0019749), and the National Cancer Institute, National Institute of Allergy and Infectious Diseases, and National Institute of General Medical Sciences of the National Institutes of Health under grant R01GM133198.