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- PDB-8paw: Crystal structure of MST1 with a MAP4K1 SMOL inhibitor -

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Basic information

Entry
Database: PDB / ID: 8paw
TitleCrystal structure of MST1 with a MAP4K1 SMOL inhibitor
ComponentsSerine/threonine-protein kinase 4 37kDa subunit
KeywordsTRANSFERASE / kinase / inhibitor / drug discovery
Function / homology
Function and homology information


positive regulation of hepatocyte apoptotic process / cell differentiation involved in embryonic placenta development / regulation of cell differentiation involved in embryonic placenta development / primitive hemopoiesis / neural tube formation / positive regulation of extrinsic apoptotic signaling pathway via death domain receptors / positive regulation of substrate-dependent cell migration, cell attachment to substrate / endocardium development / negative regulation of organ growth / hippo signaling ...positive regulation of hepatocyte apoptotic process / cell differentiation involved in embryonic placenta development / regulation of cell differentiation involved in embryonic placenta development / primitive hemopoiesis / neural tube formation / positive regulation of extrinsic apoptotic signaling pathway via death domain receptors / positive regulation of substrate-dependent cell migration, cell attachment to substrate / endocardium development / negative regulation of organ growth / hippo signaling / Signaling by Hippo / organ growth / branching involved in blood vessel morphogenesis / hepatocyte apoptotic process / regulation of MAPK cascade / extrinsic apoptotic signaling pathway via death domain receptors / positive regulation of fat cell differentiation / canonical Wnt signaling pathway / keratinocyte differentiation / protein serine/threonine kinase activator activity / epithelial cell proliferation / central nervous system development / protein tetramerization / negative regulation of canonical Wnt signaling pathway / cell morphogenesis / protein import into nucleus / negative regulation of epithelial cell proliferation / positive regulation of protein binding / positive regulation of peptidyl-serine phosphorylation / peptidyl-serine phosphorylation / RNA polymerase II-specific DNA-binding transcription factor binding / protein autophosphorylation / nuclear body / protein stabilization / non-specific serine/threonine protein kinase / protein kinase activity / intracellular signal transduction / positive regulation of protein phosphorylation / positive regulation of apoptotic process / protein phosphorylation / protein serine kinase activity / protein serine/threonine kinase activity / apoptotic process / magnesium ion binding / signal transduction / protein homodimerization activity / protein-containing complex / nucleoplasm / ATP binding / identical protein binding / nucleus / cytoplasm / cytosol
Similarity search - Function
Mst1 SARAH domain / C terminal SARAH domain of Mst1 / SARAH domain / SARAH domain profile. / p53-like tetramerisation domain superfamily / Protein kinase domain / Serine/Threonine protein kinases, catalytic domain / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. ...Mst1 SARAH domain / C terminal SARAH domain of Mst1 / SARAH domain / SARAH domain profile. / p53-like tetramerisation domain superfamily / Protein kinase domain / Serine/Threonine protein kinases, catalytic domain / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily
Similarity search - Domain/homology
ASPARTIC ACID / : / Serine/threonine-protein kinase 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.14 Å
AuthorsFriberg, A.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: To Be Published
Title: Identification and optimization of Azaindole based MAP4K1 Inhibitors and the discovery of BAY-405
Authors: Friberg, A. / Mowat, J. / Offringa, R.
History
DepositionJun 8, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jun 26, 2024Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Serine/threonine-protein kinase 4 37kDa subunit
B: Serine/threonine-protein kinase 4 37kDa subunit
hetero molecules


Theoretical massNumber of molelcules
Total (without water)72,8929
Polymers71,1912
Non-polymers1,7017
Water5,495305
1
A: Serine/threonine-protein kinase 4 37kDa subunit
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,5135
Polymers35,5961
Non-polymers9174
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Serine/threonine-protein kinase 4 37kDa subunit
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,3804
Polymers35,5961
Non-polymers7843
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)75.447, 105.627, 110.563
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

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Protein , 1 types, 2 molecules AB

#1: Protein Serine/threonine-protein kinase 4 37kDa subunit / MST1/N


Mass: 35595.711 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: STK4, KRS2, MST1 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: Q13043

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Non-polymers , 5 types, 312 molecules

#2: Chemical ChemComp-ASP / ASPARTIC ACID


Type: L-peptide linking / Mass: 133.103 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C4H7NO4
#3: Chemical ChemComp-XQL / 1-[3,5-bis(fluoranyl)-4-[[3-(1-propan-2-ylpyrazol-3-yl)-1~{H}-pyrrolo[2,3-b]pyridin-4-yl]oxy]phenyl]-3-(2-methoxyethyl)urea


Mass: 470.472 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C23H24F2N6O3 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O3
#5: Chemical ChemComp-CXS / 3-CYCLOHEXYL-1-PROPYLSULFONIC ACID


Mass: 221.317 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C9H19NO3S / Comment: pH buffer*YM
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 305 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 3.09 Å3/Da / Density % sol: 60.25 %
Crystal growTemperature: 295 K / Method: vapor diffusion, hanging drop / Details: 1.4 M NH4SO4, 0.3 M LiSO4, 0.1 M CAPS pH 9.8

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: PETRA III, DESY / Beamline: P11 / Wavelength: 1.0332 Å
DetectorType: DECTRIS EIGER2 X 16M / Detector: PIXEL / Date: Apr 10, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.0332 Å / Relative weight: 1
ReflectionResolution: 2.14→48.98 Å / Num. obs: 49164 / % possible obs: 99.1 % / Redundancy: 7.2 % / Biso Wilson estimate: 39 Å2 / CC1/2: 0.998 / Rrim(I) all: 0.106 / Net I/σ(I): 14.81
Reflection shellResolution: 2.14→2.27 Å / Redundancy: 6.8 % / Mean I/σ(I) obs: 2.32 / Num. unique obs: 7474 / CC1/2: 0.813 / Rrim(I) all: 0.761 / % possible all: 94.6

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Processing

Software
NameVersionClassification
REFMAC5.8.0267refinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing
Cootmodel building
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.14→48.98 Å / Cor.coef. Fo:Fc: 0.95 / Cor.coef. Fo:Fc free: 0.936 / SU B: 7.297 / SU ML: 0.1 / Cross valid method: THROUGHOUT / ESU R: 0.177 / ESU R Free: 0.158 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.22581 2100 4.3 %RANDOM
Rwork0.19458 ---
obs0.19591 47064 99.05 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 36.335 Å2
Baniso -1Baniso -2Baniso -3
1-0.68 Å20 Å2-0 Å2
2---0.38 Å20 Å2
3----0.31 Å2
Refinement stepCycle: 1 / Resolution: 2.14→48.98 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4423 0 116 305 4844
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0134634
X-RAY DIFFRACTIONr_bond_other_d0.0010.0164457
X-RAY DIFFRACTIONr_angle_refined_deg1.6021.6686280
X-RAY DIFFRACTIONr_angle_other_deg1.2671.58910258
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.6585553
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.98823.581215
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.93915814
X-RAY DIFFRACTIONr_dihedral_angle_4_deg21.931520
X-RAY DIFFRACTIONr_chiral_restr0.0790.2616
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.025057
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02957
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it1.4582.8552227
X-RAY DIFFRACTIONr_mcbond_other1.4582.8542226
X-RAY DIFFRACTIONr_mcangle_it2.2844.2632775
X-RAY DIFFRACTIONr_mcangle_other2.2844.2642776
X-RAY DIFFRACTIONr_scbond_it2.0223.1962407
X-RAY DIFFRACTIONr_scbond_other2.0213.1972408
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other3.2814.6743506
X-RAY DIFFRACTIONr_long_range_B_refined5.16133.7515182
X-RAY DIFFRACTIONr_long_range_B_other5.12733.4235107
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
Refine LS restraints NCS

Ens-ID: 1 / Number: 8340 / Refine-ID: X-RAY DIFFRACTION / Type: interatomic distance / Rms dev position: 0.1 Å / Weight position: 0.05

Dom-IDAuth asym-ID
1A
2B
LS refinement shellResolution: 2.14→2.19 Å
RfactorNum. reflection% reflection
Rfree0.292 136 -
Rwork0.279 3048 -
obs--88.32 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
10.47-0.2318-0.02890.86270.39180.98680.00010.01740.03620.0548-0.04380.12020.0899-0.07370.04360.0867-0.02580.01410.0107-0.00490.02942.4370.916.933
20.73220.1559-0.02130.7595-0.05710.98360.0456-0.0102-0.02910.00060.01620.0935-0.027-0.1604-0.06180.07320.0213-0.00980.03110.00980.0191.039-2.48741.103
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A23 - 298
2X-RAY DIFFRACTION1A401 - 402
3X-RAY DIFFRACTION2B14 - 299
4X-RAY DIFFRACTION2B1001

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