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- PDB-6fxk: Crystal Structure of full-length Human Lysyl Hydroxylase LH3 -

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Entry
Database: PDB / ID: 6fxk
TitleCrystal Structure of full-length Human Lysyl Hydroxylase LH3
ComponentsProcollagen-lysine,2-oxoglutarate 5-dioxygenase 3
KeywordsTRANSFERASE / Lysyl Hydroxylase / Galacosyltransferase / Glucosyltransferase / Collagen
Function / homology
Function and homology information


procollagen galactosyltransferase / procollagen glucosyltransferase / peptidyl-lysine hydroxylation / procollagen glucosyltransferase activity / hydroxylysine biosynthetic process / procollagen galactosyltransferase activity / procollagen-lysine 5-dioxygenase / procollagen-lysine 5-dioxygenase activity / basement membrane assembly / epidermis morphogenesis ...procollagen galactosyltransferase / procollagen glucosyltransferase / peptidyl-lysine hydroxylation / procollagen glucosyltransferase activity / hydroxylysine biosynthetic process / procollagen galactosyltransferase activity / procollagen-lysine 5-dioxygenase / procollagen-lysine 5-dioxygenase activity / basement membrane assembly / epidermis morphogenesis / Collagen biosynthesis and modifying enzymes / collagen metabolic process / endothelial cell morphogenesis / protein O-linked glycosylation / L-ascorbic acid binding / collagen fibril organization / neural tube development / small molecule binding / lung morphogenesis / rough endoplasmic reticulum / trans-Golgi network / vasodilation / protein localization / collagen-containing extracellular matrix / in utero embryonic development / iron ion binding / endoplasmic reticulum lumen / endoplasmic reticulum membrane / Golgi apparatus / endoplasmic reticulum / extracellular space / extracellular exosome / metal ion binding
Similarity search - Function
Procollagen-lysine 5-dioxygenase, conserved site / Lysyl hydroxylase signature. / : / Prolyl 4-hydroxylase, alpha subunit / Prolyl 4-hydroxylase alpha subunit homologues. / Isopenicillin N synthase-like, Fe(2+) 2OG dioxygenase domain / 2OG-Fe(II) oxygenase superfamily / Oxoglutarate/iron-dependent dioxygenase / Fe(2+) 2-oxoglutarate dioxygenase domain profile. / Nucleotide-diphospho-sugar transferases
Similarity search - Domain/homology
2-OXOGLUTARIC ACID / : / Multifunctional procollagen lysine hydroxylase and glycosyltransferase LH3
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / SAD / Resolution: 2.7 Å
AuthorsScietti, L. / Chiapparino, A. / De Giorgi, F. / Fumagalli, M. / Khoriauli, L. / Nergadze, S. / Basu, S. / Olieric, V. / Banushi, B. / Giulotto, E. ...Scietti, L. / Chiapparino, A. / De Giorgi, F. / Fumagalli, M. / Khoriauli, L. / Nergadze, S. / Basu, S. / Olieric, V. / Banushi, B. / Giulotto, E. / Gissen, P. / Forneris, F.
Funding support United States, Italy, 5items
OrganizationGrant numberCountry
The Giovanni Armenise-Harvard FoundationCareer Development Award United States
Cariplo Foundation2015-0768 - COME TRUE Italy
AIRC20075 Italy
European Commission MSCA-IF745934 - COTETHERS Italy
European Union - BIOSTRUCT7551, 10205 Italy
CitationJournal: Nat Commun / Year: 2018
Title: Molecular architecture of the multifunctional collagen lysyl hydroxylase and glycosyltransferase LH3.
Authors: Luigi Scietti / Antonella Chiapparino / Francesca De Giorgi / Marco Fumagalli / Lela Khoriauli / Solomon Nergadze / Shibom Basu / Vincent Olieric / Lucia Cucca / Blerida Banushi / Antonella ...Authors: Luigi Scietti / Antonella Chiapparino / Francesca De Giorgi / Marco Fumagalli / Lela Khoriauli / Solomon Nergadze / Shibom Basu / Vincent Olieric / Lucia Cucca / Blerida Banushi / Antonella Profumo / Elena Giulotto / Paul Gissen / Federico Forneris /
Abstract: Lysyl hydroxylases catalyze hydroxylation of collagen lysines, and sustain essential roles in extracellular matrix (ECM) maturation and remodeling. Malfunctions in these enzymes cause severe ...Lysyl hydroxylases catalyze hydroxylation of collagen lysines, and sustain essential roles in extracellular matrix (ECM) maturation and remodeling. Malfunctions in these enzymes cause severe connective tissue disorders. Human lysyl hydroxylase 3 (LH3/PLOD3) bears multiple enzymatic activities, as it catalyzes collagen lysine hydroxylation and also their subsequent glycosylation. Our understanding of LH3 functions is currently hampered by lack of molecular structure information. Here, we present high resolution crystal structures of full-length human LH3 in complex with cofactors and donor substrates. The elongated homodimeric LH3 architecture shows two distinct catalytic sites at the N- and C-terminal boundaries of each monomer, separated by an accessory domain. The glycosyltransferase domain displays distinguishing features compared to other known glycosyltransferases. Known disease-related mutations map in close proximity to the catalytic sites. Collectively, our results provide a structural framework characterizing the multiple functions of LH3, and the molecular mechanisms of collagen-related diseases involving human lysyl hydroxylases.
History
DepositionMar 9, 2018Deposition site: PDBE / Processing site: PDBE
Revision 1.0Aug 22, 2018Provider: repository / Type: Initial release
Revision 2.0Jul 29, 2020Group: Atomic model / Data collection ...Atomic model / Data collection / Derived calculations / Structure summary
Category: atom_site / chem_comp ...atom_site / chem_comp / entity / pdbx_branch_scheme / pdbx_chem_comp_identifier / pdbx_entity_branch / pdbx_entity_branch_descriptor / pdbx_entity_branch_link / pdbx_entity_branch_list / pdbx_entity_nonpoly / pdbx_nonpoly_scheme / pdbx_struct_assembly_gen / pdbx_struct_conn_angle / struct_asym / struct_conn / struct_site / struct_site_gen
Item: _atom_site.B_iso_or_equiv / _atom_site.Cartn_x ..._atom_site.B_iso_or_equiv / _atom_site.Cartn_x / _atom_site.Cartn_y / _atom_site.Cartn_z / _atom_site.auth_asym_id / _atom_site.auth_atom_id / _atom_site.auth_comp_id / _atom_site.auth_seq_id / _atom_site.label_asym_id / _atom_site.label_atom_id / _atom_site.label_comp_id / _atom_site.label_entity_id / _atom_site.type_symbol / _chem_comp.name / _chem_comp.type / _pdbx_entity_nonpoly.entity_id / _pdbx_entity_nonpoly.name / _pdbx_struct_assembly_gen.asym_id_list / _pdbx_struct_conn_angle.ptnr1_label_asym_id / _pdbx_struct_conn_angle.ptnr2_label_asym_id / _pdbx_struct_conn_angle.ptnr3_label_asym_id / _struct_conn.conn_type_id / _struct_conn.id / _struct_conn.pdbx_dist_value / _struct_conn.pdbx_leaving_atom_flag / _struct_conn.pdbx_role / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id
Description: Carbohydrate remediation / Provider: repository / Type: Remediation
Revision 2.1Oct 9, 2024Group: Data collection / Database references / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / database_2 / pdbx_entry_details / pdbx_modification_feature
Item: _chem_comp.pdbx_synonyms / _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Procollagen-lysine,2-oxoglutarate 5-dioxygenase 3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)83,8167
Polymers82,7841
Non-polymers1,0326
Water00
1
A: Procollagen-lysine,2-oxoglutarate 5-dioxygenase 3
hetero molecules

A: Procollagen-lysine,2-oxoglutarate 5-dioxygenase 3
hetero molecules


  • defined by author&software
  • Evidence: SAXS, SEC-SAXS data highlight presence of dimers in solution, gel filtration, gel filtration data highlight presence of dimers in solution, homology, homologous viral structures (PDB ID ...Evidence: SAXS, SEC-SAXS data highlight presence of dimers in solution, gel filtration, gel filtration data highlight presence of dimers in solution, homology, homologous viral structures (PDB ID 6AX6 and 6AX7) show identical dimer interfaces
  • 168 kDa, 2 polymers
  • Search similar-shape structures of this assembly by Omokage search (details)
Theoretical massNumber of molelcules
Total (without water)167,63214
Polymers165,5692
Non-polymers2,06312
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation4_557x,-y,-z+21
Buried area4690 Å2
ΔGint-21 kcal/mol
Surface area58710 Å2
MethodPISA
Unit cell
Length a, b, c (Å)97.290, 100.140, 226.430
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number20
Space group name H-MC2221

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Components

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Protein , 1 types, 1 molecules A

#1: Protein Procollagen-lysine,2-oxoglutarate 5-dioxygenase 3 / Lysyl hydroxylase 3 / LH3


Mass: 82784.406 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PLOD3 / Plasmid: pPuro-DHFR / Cell (production host): HeLa / Production host: Homo sapiens (human)
References: UniProt: O60568, procollagen-lysine 5-dioxygenase

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Sugars , 2 types, 2 molecules

#2: Polysaccharide 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 424.401 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DGlcpNAcb1-4DGlcpNAcb1-Glycam Condensed SequenceGMML 1.0
WURCS=2.0/1,2,1/[a2122h-1b_1-5_2*NCC/3=O]/1-1/a4-b1WURCSPDB2Glycan 1.1.0
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}}}LINUCSPDB-CARE
#6: Sugar ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Formula: C8H15NO6
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0

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Non-polymers , 3 types, 4 molecules

#3: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O3
#4: Chemical ChemComp-AKG / 2-OXOGLUTARIC ACID


Mass: 146.098 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C5H6O5 / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical ChemComp-FE2 / FE (II) ION


Mass: 55.845 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Formula: Fe / Feature type: SUBJECT OF INVESTIGATION

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Details

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: 3.1 Å3/Da / Density % sol: 60 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 7.8
Details: 600 mM sodium formate, 12% PGA-LM, 100 mM HEPES/NaOH
Temp details: cold room

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 12M / Detector: PIXEL / Date: Nov 2, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.7→69.78 Å / Num. obs: 30019 / % possible obs: 98 % / Redundancy: 3.3 % / CC1/2: 0.99 / Rmerge(I) obs: 0.166 / Rpim(I) all: 0.146 / Net I/σ(I): 4.6
Reflection shellResolution: 2.7→2.83 Å / Redundancy: 3.3 % / Rmerge(I) obs: 1.309 / Mean I/σ(I) obs: 0.7 / Num. unique obs: 3967 / CC1/2: 0.435 / Rpim(I) all: 1.163 / % possible all: 98.5

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Processing

Software
NameVersionClassification
PHENIX1.10.1_2155refinement
XDSdata reduction
Aimlessdata scaling
SHARPphasing
RefinementMethod to determine structure: SAD / Resolution: 2.7→69.78 Å / SU ML: 0.52 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 38.57
RfactorNum. reflection% reflectionSelection details
Rfree0.3087 1463 4.89 %Random selection
Rwork0.278 ---
obs0.2795 29901 97.11 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso mean: 66.5 Å2
Refinement stepCycle: LAST / Resolution: 2.7→69.78 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5491 0 65 0 5556
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0025718
X-RAY DIFFRACTIONf_angle_d0.4637773
X-RAY DIFFRACTIONf_dihedral_angle_d14.8823370
X-RAY DIFFRACTIONf_chiral_restr0.041819
X-RAY DIFFRACTIONf_plane_restr0.0051010
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.7-2.79650.49361400.4412820X-RAY DIFFRACTION97
2.7965-2.90850.43361540.41342793X-RAY DIFFRACTION97
2.9085-3.04080.3781280.38452849X-RAY DIFFRACTION97
3.0408-3.20120.40211430.36382823X-RAY DIFFRACTION98
3.2012-3.40170.37021560.33792832X-RAY DIFFRACTION98
3.4017-3.66440.34941450.3012856X-RAY DIFFRACTION97
3.6644-4.03310.32911380.26972874X-RAY DIFFRACTION98
4.0331-4.61660.26681490.22642855X-RAY DIFFRACTION97
4.6166-5.8160.26411420.2172872X-RAY DIFFRACTION96
5.816-69.80350.21731680.20882864X-RAY DIFFRACTION94
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)
10.88220.46160.01231.81730.19213.6873-0.08150.22810.0587-0.76190.02410.0886-0.9779-0.4947-0.01370.6760.2153-0.07780.639-0.03450.60661.582223.9545149.149
21.60820.32680.65413.80640.03183.7666-0.0163-0.0507-0.00850.3620.0081-0.10970.0736-0.0969-0.00030.549-0.0147-0.03620.45610.01220.525172.715635.6803183.8618
30.94640.0588-0.06172.8019-0.71133.4276-0.1207-0.14820.06380.39160.0828-0.0563-0.12470.08701.1957-0.1104-0.03560.65650.03820.556478.079318.5045220.1893
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 33 through 277 )
2X-RAY DIFFRACTION2chain 'A' and (resid 278 through 515 )
3X-RAY DIFFRACTION3chain 'A' and (resid 516 through 738 )

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