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- PDB-3r4m: Optimization of Potent, Selective, and Orally Bioavailable Pyrrol... -

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Entry
Database: PDB / ID: 3r4m
TitleOptimization of Potent, Selective, and Orally Bioavailable Pyrrolodinopyrimidine-containing Inhibitors of Heat Shock Protein 90. Identification of Development Candidate 2-amino-4-{4-chloro-2-[2-(4-fluoro-1H-pyrazol-1-yl)ethoxy]-6-methylphenyl}-N-(2,2-difluoropropyl)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxamide
ComponentsHeat shock protein HSP 90-alphaHeat shock response
KeywordsChaperone/Chaperone inhibitor / Chaperone / ATP binding / Chaperone-Chaperone inhibitor complex
Function / homology
Function and homology information


sperm mitochondrial sheath / dATP binding / Scavenging by Class F Receptors / sulfonylurea receptor binding / CTP binding / positive regulation of protein polymerization / vRNP Assembly / UTP binding / sperm plasma membrane / positive regulation of tau-protein kinase activity ...sperm mitochondrial sheath / dATP binding / Scavenging by Class F Receptors / sulfonylurea receptor binding / CTP binding / positive regulation of protein polymerization / vRNP Assembly / UTP binding / sperm plasma membrane / positive regulation of tau-protein kinase activity / protein insertion into mitochondrial outer membrane / chaperone-mediated autophagy / telomerase holoenzyme complex assembly / Rho GDP-dissociation inhibitor binding / Uptake and function of diphtheria toxin / mitochondrial transport / Drug-mediated inhibition of ERBB2 signaling / Resistance of ERBB2 KD mutants to trastuzumab / Resistance of ERBB2 KD mutants to sapitinib / Resistance of ERBB2 KD mutants to tesevatinib / Resistance of ERBB2 KD mutants to neratinib / Resistance of ERBB2 KD mutants to osimertinib / Resistance of ERBB2 KD mutants to afatinib / Resistance of ERBB2 KD mutants to AEE788 / Resistance of ERBB2 KD mutants to lapatinib / Drug resistance in ERBB2 TMD/JMD mutants / PIWI-interacting RNA (piRNA) biogenesis / TPR domain binding / non-chaperonin molecular chaperone ATPase / regulation of postsynaptic membrane neurotransmitter receptor levels / dendritic growth cone / Sema3A PAK dependent Axon repulsion / regulation of protein ubiquitination / skeletal muscle contraction / positive regulation of cell size / HSF1-dependent transactivation / telomere maintenance via telomerase / response to unfolded protein / chaperone-mediated protein complex assembly / protein unfolding / HSF1 activation / regulation of protein-containing complex assembly / Attenuation phase / RHOBTB2 GTPase cycle / positive regulation of lamellipodium assembly / eNOS activation / axonal growth cone / DNA polymerase binding / Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation / Loss of Nlp from mitotic centrosomes / Loss of proteins required for interphase microtubule organization from the centrosome / positive regulation of cardiac muscle contraction / Recruitment of mitotic centrosome proteins and complexes / cardiac muscle cell apoptotic process / positive regulation of telomerase activity / Signaling by ERBB2 / positive regulation of defense response to virus by host / endocytic vesicle lumen / response to salt stress / Recruitment of NuMA to mitotic centrosomes / Anchoring of the basal body to the plasma membrane / HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand / activation of innate immune response / nitric-oxide synthase regulator activity / response to cold / positive regulation of interferon-beta production / lysosomal lumen / Constitutive Signaling by Overexpressed ERBB2 / AURKA Activation by TPX2 / ESR-mediated signaling / protein tyrosine kinase binding / VEGFR2 mediated vascular permeability / response to cocaine / brush border membrane / ATP-dependent protein folding chaperone / Signaling by ERBB2 TMD/JMD mutants / neuron migration / Constitutive Signaling by EGFRvIII / DDX58/IFIH1-mediated induction of interferon-alpha/beta / Signaling by ERBB2 ECD mutants / tau protein binding / Signaling by ERBB2 KD Mutants / Regulation of necroptotic cell death / Regulation of actin dynamics for phagocytic cup formation / cellular response to virus / Downregulation of ERBB2 signaling / VEGFA-VEGFR2 Pathway / histone deacetylase binding / Aggrephagy / Chaperone Mediated Autophagy / positive regulation of protein import into nucleus / response to estrogen / positive regulation of protein catabolic process / The role of GTSE1 in G2/M progression after G2 checkpoint / regulation of protein localization / positive regulation of nitric oxide biosynthetic process / Regulation of PLK1 Activity at G2/M Transition / disordered domain specific binding / unfolded protein binding / melanosome
Similarity search - Function
Heat shock protein Hsp90, conserved site / Heat shock hsp90 proteins family signature. / HSP90, C-terminal domain / Heat shock protein Hsp90, N-terminal / Heat shock protein Hsp90 family / Hsp90 protein / Histidine kinase-, DNA gyrase B-, and HSP90-like ATPase / Histidine kinase-like ATPase, C-terminal domain / Heat Shock Protein 90 / Histidine kinase-, DNA gyrase B-, and HSP90-like ATPase ...Heat shock protein Hsp90, conserved site / Heat shock hsp90 proteins family signature. / HSP90, C-terminal domain / Heat shock protein Hsp90, N-terminal / Heat shock protein Hsp90 family / Hsp90 protein / Histidine kinase-, DNA gyrase B-, and HSP90-like ATPase / Histidine kinase-like ATPase, C-terminal domain / Heat Shock Protein 90 / Histidine kinase-, DNA gyrase B-, and HSP90-like ATPase / Histidine kinase-like ATPases / Histidine kinase/HSP90-like ATPase / Histidine kinase/HSP90-like ATPase superfamily / Ribosomal protein S5 domain 2-type fold / 2-Layer Sandwich / Alpha Beta
Similarity search - Domain/homology
4-CHLORO-6-(2-METHOXYPHENYL)PYRIMIDIN-2-AMINE / Heat shock protein HSP 90-alpha
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.7 Å
AuthorsAlmassy, R.J.
CitationJournal: J.Med.Chem. / Year: 2011
Title: Optimization of potent, selective, and orally bioavailable pyrrolodinopyrimidine-containing inhibitors of heat shock protein 90. Identification of development candidate 2-amino-4-{4-chloro-2- ...Title: Optimization of potent, selective, and orally bioavailable pyrrolodinopyrimidine-containing inhibitors of heat shock protein 90. Identification of development candidate 2-amino-4-{4-chloro-2-[2-(4-fluoro-1H-pyrazol-1-yl)ethoxy]-6-methylphenyl}-N-(2,2-difluoropropyl)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxamide.
Authors: Zehnder, L. / Bennett, M. / Meng, J. / Huang, B. / Ninkovic, S. / Wang, F. / Braganza, J. / Tatlock, J. / Jewell, T. / Zhou, J.Z. / Burke, B. / Wang, J. / Maegley, K. / Mehta, P.P. / Yin, M. ...Authors: Zehnder, L. / Bennett, M. / Meng, J. / Huang, B. / Ninkovic, S. / Wang, F. / Braganza, J. / Tatlock, J. / Jewell, T. / Zhou, J.Z. / Burke, B. / Wang, J. / Maegley, K. / Mehta, P.P. / Yin, M.J. / Gajiwala, K.S. / Hickey, M.J. / Yamazaki, S. / Smith, E. / Kang, P. / Sistla, A. / Dovalsantos, E. / Gehring, M.R. / Kania, R. / Wythes, M. / Kung, P.P.
History
DepositionMar 17, 2011Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 27, 2011Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Apr 11, 2012Group: Database references
Revision 1.3Feb 21, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Heat shock protein HSP 90-alpha
hetero molecules


Theoretical massNumber of molelcules
Total (without water)25,8922
Polymers25,6571
Non-polymers2361
Water3,351186
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)54.196, 44.126, 53.263
Angle α, β, γ (deg.)90.00, 115.65, 90.00
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein Heat shock protein HSP 90-alpha / Heat shock response / Heat shock 86 kDa / HSP 86 / HSP86 / Renal carcinoma antigen NY-REN-38


Mass: 25656.768 Da / Num. of mol.: 1 / Fragment: unp residues 9-236
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HSP90AA1, HSP90A, HSPC1, HSPCA / Production host: Escherichia coli (E. coli) / References: UniProt: P07900
#2: Chemical ChemComp-WOE / 4-CHLORO-6-(2-METHOXYPHENYL)PYRIMIDIN-2-AMINE


Mass: 235.670 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C11H10ClN3O
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 186 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 2.24 Å3/Da / Density % sol: 45.03 %
Crystal growTemperature: 286 K / Method: vapor diffusion, hanging drop / pH: 5.2
Details: 30 % PEG MME 550, 0.1 M CaCl2, 0.1 M cacodylate, pH 5.2, VAPOR DIFFUSION, HANGING DROP, temperature 286K

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Data collection

DiffractionMean temperature: 98 K
Diffraction sourceSource: ROTATING ANODE / Type: ENRAF-NONIUS FR591 / Wavelength: 1.5418 Å
DetectorType: MAR scanner 345 mm plate / Detector: IMAGE PLATE / Date: Apr 30, 2004 / Details: Mirrors
RadiationMonochromator: Mirros / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 1.7→24.4 Å / Num. all: 20999 / Num. obs: 20874 / % possible obs: 83.7 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 3.6 % / Biso Wilson estimate: 18.4 Å2 / Rmerge(I) obs: 0.047 / Rsym value: 0.047 / Net I/σ(I): 27.2
Reflection shellResolution: 1.7→1.76 Å / Redundancy: 3.2 % / Rmerge(I) obs: 0.083 / Mean I/σ(I) obs: 13.4 / Num. unique all: 2318 / Rsym value: 0.083 / % possible all: 93.4

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Processing

Software
NameClassification
MAR345dtbdata collection
CNXrefinement
DENZOdata reduction
SCALEPACKdata scaling
CNXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.7→24.4 Å / Rfactor Rfree error: 0.007 / Data cutoff high absF: 1756960.45 / Data cutoff low absF: 0 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.223 1005 4.8 %RANDOM
Rwork0.194 ---
all0.196 20995 --
obs0.196 20870 82.9 %-
Solvent computationSolvent model: FLAT MODEL / Bsol: 49.3314 Å2 / ksol: 0.418049 e/Å3
Displacement parametersBiso mean: 17.4 Å2
Baniso -1Baniso -2Baniso -3
1--0.56 Å20 Å2-1.16 Å2
2---0.98 Å20 Å2
3---1.54 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.21 Å0.18 Å
Luzzati d res low-5 Å
Luzzati sigma a0.09 Å-0.04 Å
Refinement stepCycle: LAST / Resolution: 1.7→24.4 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1695 0 16 186 1897
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.004
X-RAY DIFFRACTIONc_angle_deg0.8
X-RAY DIFFRACTIONc_dihedral_angle_d20.1
X-RAY DIFFRACTIONc_improper_angle_d0.61
X-RAY DIFFRACTIONc_mcbond_it1.231.5
X-RAY DIFFRACTIONc_mcangle_it1.882
X-RAY DIFFRACTIONc_scbond_it2.132
X-RAY DIFFRACTIONc_scangle_it3.212.5
Refine LS restraints NCSNCS model details: NONE
LS refinement shellResolution: 1.7→1.81 Å / Rfactor Rfree error: 0.023 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.295 168 4.5 %
Rwork0.23 3594 -
obs-3594 90.4 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1protein_rep.paraprotein.top
X-RAY DIFFRACTION2dna-rna_rep.paradna-rna.top
X-RAY DIFFRACTION3water_rep.paramwater.top
X-RAY DIFFRACTION4ion.paramion.top
X-RAY DIFFRACTION5q52.paramq52.top

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