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- PDB-8b7h: Crystal structure of human Gremlin-1 in complex with Fab -

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Basic information

Entry
Database: PDB / ID: 8b7h
TitleCrystal structure of human Gremlin-1 in complex with Fab
Components
  • Fab antibody fragment (heavy chain)
  • Fab antibody fragment (light chain)
  • Gremlin-1
KeywordsSIGNALING PROTEIN / Inhibitor / glycoprotein / cysteine knot-secreted protein
Function / homology
Function and homology information


negative regulation of bone remodeling / sequestering of BMP from receptor via BMP binding / mesenchymal to epithelial transition involved in metanephros morphogenesis / positive regulation of peptidyl-tyrosine autophosphorylation / negative regulation of monocyte chemotaxis / determination of dorsal identity / ureteric bud formation / negative regulation of osteoclast proliferation / morphogen activity / negative regulation of bone mineralization involved in bone maturation ...negative regulation of bone remodeling / sequestering of BMP from receptor via BMP binding / mesenchymal to epithelial transition involved in metanephros morphogenesis / positive regulation of peptidyl-tyrosine autophosphorylation / negative regulation of monocyte chemotaxis / determination of dorsal identity / ureteric bud formation / negative regulation of osteoclast proliferation / morphogen activity / negative regulation of bone mineralization involved in bone maturation / BMP binding / negative regulation of bone trabecula formation / Formation of the ureteric bud / negative regulation of osteoblast proliferation / proximal/distal pattern formation / regulation of epithelial to mesenchymal transition / negative regulation of bone mineralization / cardiac muscle cell myoblast differentiation / positive regulation of branching involved in ureteric bud morphogenesis / cardiac muscle cell differentiation / vascular endothelial growth factor receptor 2 binding / cell migration involved in sprouting angiogenesis / negative regulation of chondrocyte differentiation / positive regulation of signaling receptor activity / collagen fibril organization / embryonic limb morphogenesis / limb development / regulation of focal adhesion assembly / transmembrane receptor protein tyrosine kinase activator activity / negative regulation of SMAD protein signal transduction / : / positive regulation of receptor internalization / negative regulation of BMP signaling pathway / negative regulation of osteoblast differentiation / cytokine activity / animal organ morphogenesis / negative regulation of canonical Wnt signaling pathway / cell morphogenesis / negative regulation of cell growth / positive regulation of non-canonical NF-kappaB signal transduction / positive regulation of angiogenesis / cell-cell signaling / collagen-containing extracellular matrix / receptor ligand activity / negative regulation of DNA-templated transcription / positive regulation of cell population proliferation / negative regulation of apoptotic process / cell surface / signal transduction / protein homodimerization activity / positive regulation of transcription by RNA polymerase II / extracellular space
Similarity search - Function
Gremlin-1/2 / DAN / DAN domain / Cystine knot, C-terminal / C-terminal cystine knot-like domain (CTCK) / Cystine-knot cytokine
Similarity search - Domain/homology
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.95 Å
AuthorsSchulze, M.-S. / Martinez-Fleites, C.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Mabs / Year: 2023
Title: Discovery of ginisortamab, a potent and novel anti-gremlin-1 antibody in clinical development for the treatment of cancer.
Authors: Davies, G.C.G. / Dedi, N. / Jones, P.S. / Kevorkian, L. / McMillan, D. / Ottone, C. / Schulze, M.E.D. / Scott-Tucker, A. / Tewari, R. / West, S. / Wright, M. / Rowley, T.F.
History
DepositionSep 30, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 27, 2023Provider: repository / Type: Initial release
Revision 1.1Oct 16, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
L: Fab antibody fragment (light chain)
H: Fab antibody fragment (heavy chain)
A: Gremlin-1


Theoretical massNumber of molelcules
Total (without water)64,6873
Polymers64,6873
Non-polymers00
Water1,11762
1
L: Fab antibody fragment (light chain)
H: Fab antibody fragment (heavy chain)
A: Gremlin-1

L: Fab antibody fragment (light chain)
H: Fab antibody fragment (heavy chain)
A: Gremlin-1


Theoretical massNumber of molelcules
Total (without water)129,3756
Polymers129,3756
Non-polymers00
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation3_555-x,y,-z+1/21
Unit cell
Length a, b, c (Å)65.740, 80.650, 252.260
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number20
Space group name H-MC2221

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Components

#1: Antibody Fab antibody fragment (light chain)


Mass: 24197.770 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Cricetulus griseus (Chinese hamster)
#2: Antibody Fab antibody fragment (heavy chain)


Mass: 24271.008 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Cricetulus griseus (Chinese hamster)
#3: Protein Gremlin-1 / Cell proliferation-inducing gene 2 protein / Cysteine knot superfamily 1 / BMP antagonist 1 / DAN ...Cell proliferation-inducing gene 2 protein / Cysteine knot superfamily 1 / BMP antagonist 1 / DAN domain family member 2 / Down-regulated in Mos-transformed cells protein / Increased in high glucose protein 2 / IHG-2


Mass: 16218.611 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GREM1, CKTSF1B1, DAND2, DRM, PIG2 / Production host: Escherichia coli (E. coli) / References: UniProt: O60565
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 62 / Source method: isolated from a natural source / Formula: H2O
Has protein modificationY

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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: 2.58 Å3/Da / Density % sol: 52.41 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop
Details: 0.1M citric acid pH4, 1M lithium chloride and 27% polyethylene glycol (PEG) 6000

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Data collection

DiffractionMean temperature: 80 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I03 / Wavelength: 0.9786 Å
DetectorType: DECTRIS EIGER2 XE 16M / Detector: PIXEL / Date: Sep 15, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9786 Å / Relative weight: 1
ReflectionResolution: 1.95→50.96 Å / Num. obs: 48941 / % possible obs: 99.3 % / Redundancy: 5.6 % / Rmerge(I) obs: 0.051 / Net I/σ(I): 18.3
Reflection shellResolution: 1.95→2 Å / Rmerge(I) obs: 0.604 / Num. unique obs: 2672

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Processing

Software
NameVersionClassification
PHENIX(1.18.2_3874: ???)refinement
PDB_EXTRACT3.27data extraction
XDSdata reduction
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4JPH

4jph


Resolution: 1.95→50.96 Å / SU ML: 0.25 / Cross valid method: THROUGHOUT / σ(F): 1.35 / Phase error: 27.82 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.275 2472 5.05 %
Rwork0.2651 --
obs0.2656 48941 99.09 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.95→50.96 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3977 0 0 62 4039
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0114065
X-RAY DIFFRACTIONf_angle_d1.565517
X-RAY DIFFRACTIONf_dihedral_angle_d22.5311471
X-RAY DIFFRACTIONf_chiral_restr0.094619
X-RAY DIFFRACTIONf_plane_restr0.008703
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.95-1.990.3671480.33382524X-RAY DIFFRACTION99
1.99-2.030.32641530.30692496X-RAY DIFFRACTION98
2.03-2.070.28551400.31372550X-RAY DIFFRACTION99
2.07-2.120.30191250.29332551X-RAY DIFFRACTION99
2.12-2.170.28081330.28762582X-RAY DIFFRACTION99
2.17-2.230.29381100.28842521X-RAY DIFFRACTION99
2.23-2.30.30051560.28972529X-RAY DIFFRACTION99
2.3-2.370.30931420.29182610X-RAY DIFFRACTION99
2.37-2.460.27251360.28982545X-RAY DIFFRACTION100
2.46-2.560.31511350.30262565X-RAY DIFFRACTION99
2.56-2.670.31851430.28652550X-RAY DIFFRACTION100
2.67-2.810.35021240.2972581X-RAY DIFFRACTION99
2.81-2.990.30391240.28762625X-RAY DIFFRACTION99
2.99-3.220.27461280.28162611X-RAY DIFFRACTION100
3.22-3.540.27171360.26842603X-RAY DIFFRACTION100
3.54-4.060.29061420.25632645X-RAY DIFFRACTION100
4.06-5.110.21541400.21132647X-RAY DIFFRACTION99
5.11-50.960.24571570.24032734X-RAY DIFFRACTION99

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