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- PDB-6h6r: Fragment Derived XIAP inhibitor -

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Basic information

Entry
Database: PDB / ID: 6h6r
TitleFragment Derived XIAP inhibitor
ComponentsE3 ubiquitin-protein ligase XIAP
KeywordsAPOPTOSIS / inhibitor of apoptosis / caspase inhibitor zinc binding domain
Function / homology
Function and homology information


endopeptidase regulator activity / regulation of apoptosis involved in tissue homeostasis / inhibition of cysteine-type endopeptidase activity / positive regulation of protein linear polyubiquitination / regulation of BMP signaling pathway / copper ion homeostasis / nucleotide-binding oligomerization domain containing 1 signaling pathway / regulation of nucleotide-binding domain, leucine rich repeat containing receptor signaling pathway / protein serine/threonine kinase binding / nucleotide-binding oligomerization domain containing 2 signaling pathway ...endopeptidase regulator activity / regulation of apoptosis involved in tissue homeostasis / inhibition of cysteine-type endopeptidase activity / positive regulation of protein linear polyubiquitination / regulation of BMP signaling pathway / copper ion homeostasis / nucleotide-binding oligomerization domain containing 1 signaling pathway / regulation of nucleotide-binding domain, leucine rich repeat containing receptor signaling pathway / protein serine/threonine kinase binding / nucleotide-binding oligomerization domain containing 2 signaling pathway / SMAC, XIAP-regulated apoptotic response / Regulation of the apoptosome activity / Activation of caspases through apoptosome-mediated cleavage / SMAC (DIABLO) binds to IAPs / SMAC(DIABLO)-mediated dissociation of IAP:caspase complexes / TNFR1-induced proapoptotic signaling / regulation of innate immune response / RIPK1-mediated regulated necrosis / cysteine-type endopeptidase inhibitor activity / protein K63-linked ubiquitination / cysteine-type endopeptidase inhibitor activity involved in apoptotic process / positive regulation of type I interferon production / negative regulation of tumor necrosis factor-mediated signaling pathway / Regulation of PTEN localization / TNFR1-induced NF-kappa-B signaling pathway / positive regulation of protein ubiquitination / Deactivation of the beta-catenin transactivating complex / Regulation of TNFR1 signaling / positive regulation of JNK cascade / RING-type E3 ubiquitin transferase / negative regulation of cysteine-type endopeptidase activity involved in apoptotic process / Regulation of necroptotic cell death / Wnt signaling pathway / Regulation of PTEN stability and activity / ubiquitin-protein transferase activity / positive regulation of canonical Wnt signaling pathway / ubiquitin protein ligase activity / regulation of cell population proliferation / regulation of inflammatory response / neuron apoptotic process / regulation of apoptotic process / positive regulation of canonical NF-kappaB signal transduction / regulation of cell cycle / defense response to bacterium / DNA damage response / negative regulation of apoptotic process / nucleoplasm / identical protein binding / metal ion binding / nucleus / cytosol / cytoplasm
Similarity search - Function
XIAP/BIRC8, UBA domain / : / BIRC2/3-like, UBA domain / Inhibitor Of Apoptosis Protein (2mihbC-IAP-1); Chain A / Inhibitor Of Apoptosis Protein (2mihbC-IAP-1); Chain A / BIR repeat. / BIR repeat / Inhibitor of Apoptosis domain / BIR repeat profile. / Baculoviral inhibition of apoptosis protein repeat ...XIAP/BIRC8, UBA domain / : / BIRC2/3-like, UBA domain / Inhibitor Of Apoptosis Protein (2mihbC-IAP-1); Chain A / Inhibitor Of Apoptosis Protein (2mihbC-IAP-1); Chain A / BIR repeat. / BIR repeat / Inhibitor of Apoptosis domain / BIR repeat profile. / Baculoviral inhibition of apoptosis protein repeat / Zinc finger, C3HC4 type (RING finger) / Death-like domain superfamily / Ring finger / Zinc finger RING-type profile. / Zinc finger, RING-type / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-FUE / E3 ubiquitin-protein ligase XIAP
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / FOURIER SYNTHESIS / Resolution: 2.03 Å
AuthorsWilliams, P.A.
CitationJournal: J. Med. Chem. / Year: 2018
Title: A Fragment-Derived Clinical Candidate for Antagonism of X-Linked and Cellular Inhibitor of Apoptosis Proteins: 1-(6-[(4-Fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1 H,2 H,3 H- ...Title: A Fragment-Derived Clinical Candidate for Antagonism of X-Linked and Cellular Inhibitor of Apoptosis Proteins: 1-(6-[(4-Fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1 H,2 H,3 H-pyrrolo[3,2- b]pyridin-1-yl)-2-[(2 R,5 R)-5-methyl-2-([(3R)-3-methylmorpholin-4-yl]methyl)piperazin-1-yl]ethan-1-one (ASTX660).
Authors: Johnson, C.N. / Ahn, J.S. / Buck, I.M. / Chiarparin, E. / Day, J.E.H. / Hopkins, A. / Howard, S. / Lewis, E.J. / Martins, V. / Millemaggi, A. / Munck, J.M. / Page, L.W. / Peakman, T. / ...Authors: Johnson, C.N. / Ahn, J.S. / Buck, I.M. / Chiarparin, E. / Day, J.E.H. / Hopkins, A. / Howard, S. / Lewis, E.J. / Martins, V. / Millemaggi, A. / Munck, J.M. / Page, L.W. / Peakman, T. / Reader, M. / Rich, S.J. / Saxty, G. / Smyth, T. / Thompson, N.T. / Ward, G.A. / Williams, P.A. / Wilsher, N.E. / Chessari, G.
History
DepositionJul 30, 2018Deposition site: PDBE / Processing site: PDBE
Revision 1.0Aug 22, 2018Provider: repository / Type: Initial release
Revision 1.1Sep 5, 2018Group: Data collection / Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: E3 ubiquitin-protein ligase XIAP
hetero molecules


Theoretical massNumber of molelcules
Total (without water)15,2054
Polymers14,5751
Non-polymers6303
Water3,549197
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: mass spectrometry
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area120 Å2
ΔGint-7 kcal/mol
Surface area6640 Å2
MethodPISA
Unit cell
Length a, b, c (Å)71.352, 71.352, 105.569
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number91
Space group name H-MP4122
Components on special symmetry positions
IDModelComponents
11A-351-

CYS

21A-402-

NA

31A-553-

HOH

41A-645-

HOH

51A-675-

HOH

61A-684-

HOH

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Components

#1: Protein E3 ubiquitin-protein ligase XIAP / Baculoviral IAP repeat-containing protein 4 / IAP-like protein / hILP / Inhibitor of apoptosis ...Baculoviral IAP repeat-containing protein 4 / IAP-like protein / hILP / Inhibitor of apoptosis protein 3 / hIAP3 / RING-type E3 ubiquitin transferase XIAP / X-linked inhibitor of apoptosis protein / X-linked IAP


Mass: 14575.300 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: protein domain / Source: (gene. exp.) Homo sapiens (human) / Gene: XIAP, API3, BIRC4, IAP3 / Production host: Escherichia coli BL21(DE3) (bacteria)
References: UniProt: P98170, RING-type E3 ubiquitin transferase
#2: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
#3: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Na
#4: Chemical ChemComp-FUE / 2-[[(2~{R},5~{R})-1-[2-[6-[(4-fluorophenyl)methyl]-3,3-dimethyl-2~{H}-pyrrolo[3,2-b]pyridin-1-yl]-2-oxidanylidene-ethyl]-5-methyl-piperazin-2-yl]methyl]-3~{H}-isoindol-1-one


Mass: 541.659 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C32H36FN5O2
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 197 / 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

Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 8 / Details: 3.1M NaCl .1M pH=8 HEPES/NaOH

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-X / Wavelength: 1.54187 Å
DetectorType: RIGAKU SATURN 944 / Detector: CCD / Date: Nov 15, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54187 Å / Relative weight: 1
ReflectionResolution: 2.02→71.654 Å / Num. obs: 18258 / % possible obs: 98.7 % / Redundancy: 3.5 % / Biso Wilson estimate: 34.6 Å2 / Rrim(I) all: 0.067 / Net I/σ(I): 14.2
Reflection shellResolution: 2.02→2.03 Å / Mean I/σ(I) obs: 1.4 / Num. unique obs: 211 / Rrim(I) all: 0.791 / % possible all: 91.6

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Processing

Software
NameVersionClassification
BUSTER2.11.7refinement
XDSdata reduction
SCALAdata scaling
BUSTERphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 2.03→29.56 Å / Cor.coef. Fo:Fc: 0.927 / Cor.coef. Fo:Fc free: 0.911 / SU R Cruickshank DPI: 0.143 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.144 / SU Rfree Blow DPI: 0.136 / SU Rfree Cruickshank DPI: 0.123
RfactorNum. reflection% reflectionSelection details
Rfree0.243 948 5.27 %RANDOM
Rwork0.212 ---
obs0.214 17994 98.6 %-
Displacement parametersBiso mean: 41.736 Å2
Baniso -1Baniso -2Baniso -3
1-1.5233 Å20 Å20 Å2
2--1.5233 Å20 Å2
3----3.0466 Å2
Refine analyzeLuzzati coordinate error obs: 0.27 Å
Refinement stepCycle: 1 / Resolution: 2.03→29.56 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms873 0 42 197 1112
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0121809HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.063256HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d382SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes24HARMONIC2
X-RAY DIFFRACTIONt_gen_planes271HARMONIC16
X-RAY DIFFRACTIONt_it1809HARMONIC20
X-RAY DIFFRACTIONt_nbd0SEMIHARMONIC5
X-RAY DIFFRACTIONt_omega_torsion6.3
X-RAY DIFFRACTIONt_other_torsion15.89
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion110SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact2152SEMIHARMONIC4
LS refinement shellResolution: 2.03→2.15 Å / Total num. of bins used: 9
RfactorNum. reflection% reflection
Rfree0.2988 135 4.96 %
Rwork0.2635 2589 -
all0.2653 2724 -
obs--94.65 %
Refinement TLS params.Method: refined / Origin x: -17.4235 Å / Origin y: -28.3687 Å / Origin z: -4.0667 Å
111213212223313233
T-0.058 Å2-0.0165 Å2-0.036 Å2-0.055 Å2-0.0558 Å2---0.0937 Å2
L2.888 °2-0.3829 °20.2661 °2-0.8561 °2-1.1391 °2--1.0372 °2
S0.0943 Å °-0.2978 Å °0.0029 Å °0.1455 Å °0.002 Å °-0.0339 Å °0.0053 Å °0.1869 Å °-0.0963 Å °
Refinement TLS groupSelection details: { A|248 - A|354 }

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