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- PDB-6fmf: Neuropilin-1 b1 domain in complex with EG01377; 2.8 Angstrom structure -

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Basic information

Entry
Database: PDB / ID: 6fmf
TitleNeuropilin-1 b1 domain in complex with EG01377; 2.8 Angstrom structure
ComponentsNeuropilin-1Neuropilin 1
KeywordsSIGNALING PROTEIN / small molecule inhibitor / VEGF signaling / semaphorin signaling / angiogenesis / discoiding domain
Function / homology
Function and homology information


positive regulation of cytokine activity / endothelial tip cell fate specification / basal dendrite development / protein localization to early endosome / otic placode development / neurofilament / basal dendrite arborization / dichotomous subdivision of terminal units involved in salivary gland branching / retina vasculature morphogenesis in camera-type eye / regulation of vascular endothelial growth factor receptor signaling pathway ...positive regulation of cytokine activity / endothelial tip cell fate specification / basal dendrite development / protein localization to early endosome / otic placode development / neurofilament / basal dendrite arborization / dichotomous subdivision of terminal units involved in salivary gland branching / retina vasculature morphogenesis in camera-type eye / regulation of vascular endothelial growth factor receptor signaling pathway / vestibulocochlear nerve structural organization / dorsal root ganglion morphogenesis / ventral trunk neural crest cell migration / sympathetic neuron projection guidance / facioacoustic ganglion development / trigeminal ganglion development / trigeminal nerve structural organization / sensory neuron axon guidance / facial nerve structural organization / gonadotrophin-releasing hormone neuronal migration to the hypothalamus / postsynapse organization / branchiomotor neuron axon guidance / renal artery morphogenesis / axon extension involved in axon guidance / VEGF-activated neuropilin signaling pathway / negative regulation of axon extension involved in axon guidance / sympathetic neuron projection extension / motor neuron migration / Neurophilin interactions with VEGF and VEGFR / endothelial cell chemotaxis / vascular endothelial growth factor binding / sympathetic ganglion development / axonogenesis involved in innervation / neural crest cell migration involved in autonomic nervous system development / positive regulation of axon extension involved in axon guidance / CHL1 interactions / vascular endothelial growth factor receptor activity / substrate-dependent cell migration, cell extension / semaphorin receptor complex / regulation of vesicle-mediated transport / Signaling by ROBO receptors / SEMA3A-Plexin repulsion signaling by inhibiting Integrin adhesion / angiogenesis involved in coronary vascular morphogenesis / hepatocyte growth factor receptor signaling pathway / neuropilin signaling pathway / coronary artery morphogenesis / outflow tract septum morphogenesis / regulation of Cdc42 protein signal transduction / semaphorin receptor activity / commissural neuron axon guidance / CRMPs in Sema3A signaling / motor neuron axon guidance / cell migration involved in sprouting angiogenesis / retinal ganglion cell axon guidance / artery morphogenesis / axonal fasciculation / sprouting angiogenesis / neural crest cell migration / positive regulation of filopodium assembly / branching involved in blood vessel morphogenesis / cellular response to hepatocyte growth factor stimulus / positive regulation of cell migration involved in sprouting angiogenesis / positive chemotaxis / cytokine binding / positive regulation of smooth muscle cell migration / growth factor binding / sorting endosome / positive regulation of focal adhesion assembly / semaphorin-plexin signaling pathway / Sema3A PAK dependent Axon repulsion / platelet-derived growth factor receptor signaling pathway / cellular response to vascular endothelial growth factor stimulus / vasculogenesis / vascular endothelial growth factor receptor signaling pathway / coreceptor activity / positive regulation of substrate adhesion-dependent cell spreading / positive regulation of stress fiber assembly / positive regulation of endothelial cell proliferation / GTPase activator activity / positive regulation of endothelial cell migration / Signal transduction by L1 / integrin-mediated signaling pathway / axon guidance / mitochondrial membrane / negative regulation of extrinsic apoptotic signaling pathway / animal organ morphogenesis / neuron migration / response to wounding / positive regulation of angiogenesis / positive regulation of peptidyl-tyrosine phosphorylation / cell-cell signaling / heparin binding / cytoplasmic vesicle / postsynaptic membrane / angiogenesis / negative regulation of neuron apoptotic process / Attachment and Entry / positive regulation of ERK1 and ERK2 cascade / receptor complex / early endosome
Similarity search - Function
Neuropilin / Neuropilin, C-terminal / C-terminal domain of neuropilin glycoprotein / MAM domain signature. / Domain in meprin, A5, receptor protein tyrosine phosphatase mu (and others) / MAM domain, meprin/A5/mu / MAM domain / Coagulation factors 5/8 type C domain (FA58C) signature 2. / MAM domain profile. / CUB domain ...Neuropilin / Neuropilin, C-terminal / C-terminal domain of neuropilin glycoprotein / MAM domain signature. / Domain in meprin, A5, receptor protein tyrosine phosphatase mu (and others) / MAM domain, meprin/A5/mu / MAM domain / Coagulation factors 5/8 type C domain (FA58C) signature 2. / MAM domain profile. / CUB domain / Domain first found in C1r, C1s, uEGF, and bone morphogenetic protein. / CUB domain / CUB domain profile. / Coagulation factors 5/8 type C domain (FA58C) signature 1. / Spermadhesin, CUB domain superfamily / Coagulation factor 5/8 C-terminal domain, discoidin domain / Coagulation factors 5/8 type C domain (FA58C) profile. / F5/8 type C domain / Coagulation factor 5/8 C-terminal domain / Galactose-binding domain-like / Galactose-binding-like domain superfamily / Concanavalin A-like lectin/glucanase domain superfamily / Jelly Rolls / Sandwich / Mainly Beta
Similarity search - Domain/homology
Chem-DUE / trifluoroacetic acid / Neuropilin-1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.811 Å
AuthorsYelland, T. / Djordjevic, S. / Selwood, D. / Zachary, I. / Frankel, P.
Funding support United Kingdom, 2items
OrganizationGrant numberCountry
BHFRG/11/11/29050 United Kingdom
Biotechnology and Biological Sciences Research CouncilISMB DTG United Kingdom
CitationJournal: J. Med. Chem. / Year: 2018
Title: Small Molecule Neuropilin-1 Antagonists Combine Antiangiogenic and Antitumor Activity with Immune Modulation through Reduction of Transforming Growth Factor Beta (TGF beta ) Production in Regulatory T-Cells.
Authors: Powell, J. / Mota, F. / Steadman, D. / Soudy, C. / Miyauchi, J.T. / Crosby, S. / Jarvis, A. / Reisinger, T. / Winfield, N. / Evans, G. / Finniear, A. / Yelland, T. / Chou, Y.T. / Chan, A.W.E. ...Authors: Powell, J. / Mota, F. / Steadman, D. / Soudy, C. / Miyauchi, J.T. / Crosby, S. / Jarvis, A. / Reisinger, T. / Winfield, N. / Evans, G. / Finniear, A. / Yelland, T. / Chou, Y.T. / Chan, A.W.E. / O'Leary, A. / Cheng, L. / Liu, D. / Fotinou, C. / Milagre, C. / Martin, J.F. / Jia, H. / Frankel, P. / Djordjevic, S. / Tsirka, S.E. / Zachary, I.C. / Selwood, D.L.
History
DepositionJan 31, 2018Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 17, 2018Provider: repository / Type: Initial release
Revision 1.1Jan 17, 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: Neuropilin-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)18,6163
Polymers17,9171
Non-polymers6992
Water18010
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area7820 Å2
MethodPISA
Unit cell
Length a, b, c (Å)39.655, 39.655, 91.780
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number76
Space group name H-MP41

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Components

#1: Protein Neuropilin-1 / Neuropilin 1 / Vascular endothelial cell growth factor 165 receptor


Mass: 17917.291 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NRP1, NRP, VEGF165R / Production host: Escherichia coli (E. coli) / References: UniProt: O14786
#2: Chemical ChemComp-DUE / (2~{S})-2-[[3-[[5-[4-(aminomethyl)phenyl]-1-benzofuran-7-yl]sulfonylamino]thiophen-2-yl]carbonylamino]-5-carbamimidamido-pentanoic acid


Mass: 584.667 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C26H28N6O6S2 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-TFA / trifluoroacetic acid / Trifluoroacetic acid


Mass: 114.023 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2HF3O2
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 10 / 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: 2.01 Å3/Da / Density % sol: 38.92 %
Crystal growTemperature: 293.15 K / Method: vapor diffusion, hanging drop / Details: 16 % w/v PEG3350 and 200 mM ammonium chloride

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU MICROMAX-007 / Wavelength: 1.54179 Å
DetectorType: RIGAKU SATURN 944 / Detector: CCD / Date: Dec 1, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54179 Å / Relative weight: 1
ReflectionResolution: 2.8→39.65 Å / Num. obs: 3271 / % possible obs: 98.13 % / Redundancy: 12.8 % / CC1/2: 0.994 / Rmerge(I) obs: 0.18 / Rpim(I) all: 0.075 / Net I/σ(I): 10.9
Reflection shellResolution: 2.8→2.96 Å / Rmerge(I) obs: 0.35 / CC1/2: 0.938 / % possible all: 82.2

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Processing

Software
NameVersionClassification
PHENIX1.7.3_928refinement
d*TREKdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1KEX

1kex


Resolution: 2.811→20.671 Å / SU ML: 0.33 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 30.3
RfactorNum. reflection% reflection
Rfree0.2923 132 3.88 %
Rwork0.2329 --
obs0.2351 3403 98.13 %
Solvent computationShrinkage radii: 0.73 Å / VDW probe radii: 1 Å / Bsol: 0.001 Å2 / ksol: 0.296 e/Å3
Displacement parameters
Baniso -1Baniso -2Baniso -3
1--5.156 Å2-0 Å2-0 Å2
2---5.156 Å20 Å2
3----5.2159 Å2
Refinement stepCycle: LAST / Resolution: 2.811→20.671 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1229 0 47 10 1286
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0041308
X-RAY DIFFRACTIONf_angle_d1.3351776
X-RAY DIFFRACTIONf_dihedral_angle_d14.006479
X-RAY DIFFRACTIONf_chiral_restr0.07190
X-RAY DIFFRACTIONf_plane_restr0.006222
LS refinement shellResolution: 2.8112→20.6718 Å
RfactorNum. reflection% reflection
Rfree0.2923 132 -
Rwork0.2329 3271 -
obs--98 %

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