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- PDB-8v4x: Structure of MALT1 in complex with an allosteric inhibitor -

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Basic information

Entry
Database: PDB / ID: 8v4x
TitleStructure of MALT1 in complex with an allosteric inhibitor
Components
  • Inhibitor peptide
  • Mucosa-associated lymphoid tissue lymphoma translocation protein 1
KeywordsHYDROLASE/INHIBITOR / Hydrolase / allosteric inhibitor. / HYDROLASE-INHIBITOR complex
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
N-[(benzyloxy)carbonyl]-L-valyl-N~5~-[amino(iminio)methyl]-L-ornithyl-N-[(3R)-6-{[amino(iminio)methyl]amino}-1-fluoro-2-oxohexan-3-yl]-L-prolinamide / : / Mucosa-associated lymphoid tissue lymphoma translocation protein 1
Similarity search - Component
Biological speciesHomo sapiens (human)
synthetic construct (others)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.486 Å
AuthorsJudge, R.A. / Pappano, W.N.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Mol.Cancer Ther. / Year: 2024
Title: Inhibition of MALT1 and BCL2 Induces Synergistic Antitumor Activity in Models of B-Cell Lymphoma.
Authors: Plotnik, J.P. / Richardson, A.E. / Yang, H. / Rojas, E. / Bontcheva, V. / Dowell, C. / Parsons, S. / Wilson, A. / Ravanmehr, V. / Will, C. / Jung, P. / Zhu, H. / Partha, S.K. / Panchal, S.C. ...Authors: Plotnik, J.P. / Richardson, A.E. / Yang, H. / Rojas, E. / Bontcheva, V. / Dowell, C. / Parsons, S. / Wilson, A. / Ravanmehr, V. / Will, C. / Jung, P. / Zhu, H. / Partha, S.K. / Panchal, S.C. / Mali, R.S. / Kohlhapp, F.J. / McClure, R.A. / Ramathal, C.Y. / George, M.D. / Jhala, M. / Elsen, N.L. / Qiu, W. / Judge, R.A. / Pan, C. / Mastracchio, A. / Henderson, J. / Meulbroek, J.A. / Green, M.R. / Pappano, W.N.
History
DepositionNov 29, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 1, 2024Provider: repository / Type: Initial release
Revision 1.1Jul 10, 2024Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Mucosa-associated lymphoid tissue lymphoma translocation protein 1
B: Mucosa-associated lymphoid tissue lymphoma translocation protein 1
C: Mucosa-associated lymphoid tissue lymphoma translocation protein 1
D: Mucosa-associated lymphoid tissue lymphoma translocation protein 1
E: Mucosa-associated lymphoid tissue lymphoma translocation protein 1
F: Mucosa-associated lymphoid tissue lymphoma translocation protein 1
G: Inhibitor peptide
H: Inhibitor peptide
I: Inhibitor peptide
J: Inhibitor peptide
K: Inhibitor peptide
L: Inhibitor peptide
hetero molecules


Theoretical massNumber of molelcules
Total (without water)269,25316
Polymers267,34012
Non-polymers1,9144
Water6,990388
1
A: Mucosa-associated lymphoid tissue lymphoma translocation protein 1
C: Mucosa-associated lymphoid tissue lymphoma translocation protein 1
G: Inhibitor peptide
I: Inhibitor peptide
hetero molecules


  • defined by author
  • 90.1 kDa, 4 polymers
Theoretical massNumber of molelcules
Total (without water)90,0706
Polymers89,1134
Non-polymers9572
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Mucosa-associated lymphoid tissue lymphoma translocation protein 1
D: Mucosa-associated lymphoid tissue lymphoma translocation protein 1
H: Inhibitor peptide
J: Inhibitor peptide
hetero molecules


  • defined by author
  • 90.1 kDa, 4 polymers
Theoretical massNumber of molelcules
Total (without water)90,0706
Polymers89,1134
Non-polymers9572
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
E: Mucosa-associated lymphoid tissue lymphoma translocation protein 1
K: Inhibitor peptide

F: Mucosa-associated lymphoid tissue lymphoma translocation protein 1
L: Inhibitor peptide


  • defined by author
  • 89.1 kDa, 4 polymers
Theoretical massNumber of molelcules
Total (without water)89,1134
Polymers89,1134
Non-polymers00
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_545-x,y-1/2,-z1
4
F: Mucosa-associated lymphoid tissue lymphoma translocation protein 1
L: Inhibitor peptide

E: Mucosa-associated lymphoid tissue lymphoma translocation protein 1
K: Inhibitor peptide


  • defined by author
  • 89.1 kDa, 4 polymers
Theoretical massNumber of molelcules
Total (without water)89,1134
Polymers89,1134
Non-polymers00
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_555-x,y+1/2,-z1
Unit cell
Length a, b, c (Å)135.32, 78.77, 135.88
Angle α, β, γ (deg.)90, 112.52, 90
Int Tables number4
Space group name H-MP1211

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Components

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


Mass: 43859.367 Da / Num. of mol.: 6
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MALT1, MLT / Cell (production host): HEK (293-EBNA) / Cell line (production host): HEK (293-EBNA) / Production host: Homo sapiens (human)
References: UniProt: Q9UDY8, Hydrolases; Acting on peptide bonds (peptidases); Cysteine endopeptidases
#2: Protein/peptide
Inhibitor peptide


Type: Oligopeptide / Class: Inhibitor / Mass: 697.244 Da / Num. of mol.: 6 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)
References: N-[(benzyloxy)carbonyl]-L-valyl-N~5~-[amino(iminio)methyl]-L-ornithyl-N-[(3R)-6-{[amino(iminio)methyl]amino}-1-fluoro-2-oxohexan-3-yl]-L-prolinamide
#3: Chemical
ChemComp-A1AAB / N-{7-[(1S)-1-methoxyethyl]-2-methyl[1,3]thiazolo[5,4-b]pyridin-6-yl}-N'-[6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl]urea


Mass: 478.451 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C19H17F3N8O2S / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 388 / 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: 2.38 Å3/Da / Density % sol: 48.34 %
Crystal growTemperature: 290 K / Method: vapor diffusion, sitting drop / pH: 5.5 / Details: 16% (w/v) PEG 8000, 0.1 M sodium citrate pH 5.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Feb 21, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.486→125.521 Å / Num. obs: 51037 / % possible obs: 91.9 % / Redundancy: 3.4 % / CC1/2: 0.996 / Net I/σ(I): 7.2
Reflection shellResolution: 2.486→2.817 Å / Num. unique obs: 2554 / CC1/2: 0.564 / % possible all: 67.5

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Processing

Software
NameVersionClassification
BUSTER2.11.8refinement
autoPROCdata reduction
XDSdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.486→34.9 Å / Cor.coef. Fo:Fc: 0.927 / Cor.coef. Fo:Fc free: 0.861 / Cross valid method: THROUGHOUT / SU Rfree Blow DPI: 0.496
Details: Data was processed using the Global Phasing autoProc with STARANISO processing
RfactorNum. reflection% reflectionSelection details
Rfree0.2852 2471 -RANDOM
Rwork0.2092 ---
obs0.2129 51037 54.7 %-
Displacement parametersBiso mean: 43.94 Å2
Baniso -1Baniso -2Baniso -3
1-0.6928 Å20 Å21.1627 Å2
2---3.7946 Å20 Å2
3---3.1018 Å2
Refine analyzeLuzzati coordinate error obs: 0.37 Å
Refinement stepCycle: LAST / Resolution: 2.486→34.9 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms16898 0 414 388 17700
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.00717640HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.9323919HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d6141SINUSOIDAL2
X-RAY DIFFRACTIONt_gen_planes3144HARMONIC5
X-RAY DIFFRACTIONt_it17640HARMONIC10
X-RAY DIFFRACTIONt_chiral_improper_torsion2279SEMIHARMONIC5
X-RAY DIFFRACTIONt_ideal_dist_contact13359SEMIHARMONIC4
X-RAY DIFFRACTIONt_omega_torsion2.54
X-RAY DIFFRACTIONt_other_torsion20.7
LS refinement shellResolution: 2.49→2.69 Å
RfactorNum. reflection% reflection
Rfree0.3839 40 -
Rwork0.2504 --
obs0.2567 1021 5.22 %

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