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- PDB-7ak1: Human MALT1(329-729) in complex with a chromane urea containing i... -

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Basic information

Entry
Database: PDB / ID: 7ak1
TitleHuman MALT1(329-729) in complex with a chromane urea containing inhibitor
ComponentsMucosa-associated lymphoid tissue lymphoma translocation protein 1
KeywordsHYDROLASE / Inhibitor / complex / allosteric inhibitor
Function / homology
Function and homology information


polkadots / B-1 B cell differentiation / positive regulation of T-helper 17 cell differentiation / CBM complex / regulation of T cell receptor signaling pathway / response to fungus / activation of NF-kappaB-inducing kinase activity / CLEC7A/inflammasome pathway / nuclear export / B cell activation ...polkadots / B-1 B cell differentiation / positive regulation of T-helper 17 cell differentiation / CBM complex / regulation of T cell receptor signaling pathway / response to fungus / activation of NF-kappaB-inducing kinase activity / CLEC7A/inflammasome pathway / nuclear export / B cell activation / positive regulation of cysteine-type endopeptidase activity involved in apoptotic process / small molecule binding / T cell proliferation / lipopolysaccharide-mediated signaling pathway / positive regulation of interleukin-2 production / proteolysis involved in protein catabolic process / positive regulation of interleukin-1 beta production / positive regulation of protein ubiquitination / Activation of NF-kappaB in B cells / positive regulation of T cell cytokine production / CLEC7A (Dectin-1) signaling / fibrillar center / defense response / FCERI mediated NF-kB activation / ubiquitin-protein transferase activity / : / Downstream TCR signaling / peptidase activity / positive regulation of NF-kappaB transcription factor activity / T cell receptor signaling pathway / regulation of apoptotic process / positive regulation of canonical NF-kappaB signal transduction / protease binding / endopeptidase activity / Hydrolases; Acting on peptide bonds (peptidases); Cysteine endopeptidases / cysteine-type endopeptidase activity / innate immune response / negative regulation of apoptotic process / perinuclear region of cytoplasm / protein-containing complex / proteolysis / identical protein binding / nucleus / cytoplasm / cytosol
Similarity search - Function
Mucosa-associated lymphoid tissue lymphoma translocation protein 1 / MALT1, death domain / MALT1 immunoglobulin-like domain / MALT1 Ig-like domain / Immunoglobulin domain / Peptidase C14, p20 domain / Caspase family p20 domain profile. / : / Caspase domain / Caspase-like domain superfamily ...Mucosa-associated lymphoid tissue lymphoma translocation protein 1 / MALT1, death domain / MALT1 immunoglobulin-like domain / MALT1 Ig-like domain / Immunoglobulin domain / Peptidase C14, p20 domain / Caspase family p20 domain profile. / : / Caspase domain / Caspase-like domain superfamily / Immunoglobulin domain / Death-like domain superfamily / Immunoglobulin subtype 2 / Immunoglobulin C-2 Type / Immunoglobulin subtype / Immunoglobulin / Ig-like domain profile. / Immunoglobulin-like domain / Immunoglobulin-like domain superfamily / Immunoglobulin-like fold
Similarity search - Domain/homology
Chem-RJH / Mucosa-associated lymphoid tissue lymphoma translocation protein 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.507 Å
AuthorsRenatus, M.
CitationJournal: J.Med.Chem. / Year: 2020
Title: Discovery of Potent, Highly Selective, and In Vivo Efficacious, Allosteric MALT1 Inhibitors by Iterative Scaffold Morphing.
Authors: Pissot Soldermann, C. / Simic, O. / Renatus, M. / Erbel, P. / Melkko, S. / Wartmann, M. / Bigaud, M. / Weiss, A. / McSheehy, P. / Endres, R. / Santos, P. / Blank, J. / Schuffenhauer, A. / ...Authors: Pissot Soldermann, C. / Simic, O. / Renatus, M. / Erbel, P. / Melkko, S. / Wartmann, M. / Bigaud, M. / Weiss, A. / McSheehy, P. / Endres, R. / Santos, P. / Blank, J. / Schuffenhauer, A. / Bold, G. / Buschmann, N. / Zoller, T. / Altmann, E. / Manley, P.W. / Dix, I. / Buchdunger, E. / Scesa, J. / Quancard, J. / Schlapbach, A. / Bornancin, F. / Radimerski, T. / Regnier, C.H.
History
DepositionSep 29, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 9, 2020Provider: repository / Type: Initial release
Revision 1.1Dec 23, 2020Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.2Jan 31, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Mucosa-associated lymphoid tissue lymphoma translocation protein 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)46,1653
Polymers45,6791
Non-polymers4852
Water79344
1


  • Idetical with deposited unit
  • defined by software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area110 Å2
ΔGint-8 kcal/mol
Surface area16610 Å2
MethodPISA
Unit cell
Length a, b, c (Å)91.32, 56.33, 79.783
Angle α, β, γ (deg.)90, 99.77, 90
Int Tables number5
Space group name H-MC121

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Components

#1: Protein Mucosa-associated lymphoid tissue lymphoma translocation protein 1 / MALT lymphoma-associated translocation / Paracaspase


Mass: 45679.383 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MALT1, MLT / Production host: Escherichia coli (E. coli)
References: UniProt: Q9UDY8, Hydrolases; Acting on peptide bonds (peptidases); Cysteine endopeptidases
#2: Chemical ChemComp-RJH / 1-(3-chloranyl-4-methoxy-phenyl)-3-[7-[(3~{S})-3-(methoxymethyl)morpholin-4-yl]-2-methyl-pyrazolo[1,5-a]pyrimidin-6-yl]urea


Mass: 460.914 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H25ClN6O4 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 44 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 2.54 Å3/Da / Density % sol: 51.64 %
Crystal growTemperature: 294 K / Method: vapor diffusion, sitting drop / Details: 12.2 mg/ml, 25mM HEPES pH7.5, 50mM NaCL, 1mM TCEP

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 1.00001 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: Aug 15, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.00001 Å / Relative weight: 1
ReflectionResolution: 2.507→42.547 Å / Num. obs: 13066 / % possible obs: 94 % / Redundancy: 3.3 % / CC1/2: 0.997 / Rmerge(I) obs: 0.089 / Rpim(I) all: 0.057 / Rrim(I) all: 0.106 / Net I/σ(I): 7.7 / Num. measured all: 43440
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
2.507-2.5153.40.6114471320.7690.3860.7252.4100
11.558-42.5473.20.0274781510.9990.0180.03217.497.4

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Processing

Software
NameVersionClassification
BUSTERrefinement
Aimlessdata scaling
PDB_EXTRACT3.25data extraction
BUSTERphasing
XDSdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 7AK0

7ak0


Resolution: 2.507→42.55 Å / Cor.coef. Fo:Fc: 0.903 / Cor.coef. Fo:Fc free: 0.847 / SU R Cruickshank DPI: 0.671 / Cross valid method: THROUGHOUT / SU R Blow DPI: 0.624 / SU Rfree Blow DPI: 0.309 / SU Rfree Cruickshank DPI: 0.317
RfactorNum. reflection% reflectionSelection details
Rfree0.2651 614 -RANDOM
Rwork0.1962 ---
obs0.1993 13054 93.9 %-
Displacement parametersBiso mean: 51.17 Å2
Baniso -1Baniso -2Baniso -3
1--5.5272 Å20 Å214.4284 Å2
2---6.653 Å20 Å2
3---12.1803 Å2
Refine analyzeLuzzati coordinate error obs: 0.32 Å
Refinement stepCycle: LAST / Resolution: 2.507→42.55 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2783 0 33 46 2862
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0082872HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.023884HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1019SINUSOIDAL2
X-RAY DIFFRACTIONt_gen_planes480HARMONIC5
X-RAY DIFFRACTIONt_it2872HARMONIC10
X-RAY DIFFRACTIONt_chiral_improper_torsion366SEMIHARMONIC5
X-RAY DIFFRACTIONt_ideal_dist_contact2138SEMIHARMONIC4
X-RAY DIFFRACTIONt_omega_torsion3
X-RAY DIFFRACTIONt_other_torsion18.09
LS refinement shellResolution: 2.51→2.53 Å
RfactorNum. reflection% reflection
Rfree0.2537 22 -
Rwork0.2271 --
obs0.2285 436 99.31 %
Refinement TLS params.Origin x: -19.3464 Å / Origin y: -16.0609 Å / Origin z: 14.4032 Å
111213212223313233
T-0.0859 Å20.0108 Å20.0335 Å2--0.0439 Å20.0121 Å2---0.0307 Å2
L0.7766 °20.1279 °21.5954 °2-0.3569 °2-0.7084 °2--3.6594 °2
S-0.0501 Å °-0.0301 Å °-0.0064 Å °-0.0301 Å °0.075 Å °-0.1236 Å °-0.0064 Å °-0.1236 Å °-0.0249 Å °
Refinement TLS groupSelection details: { A|* }

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