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- PDB-9nrc: TMPRSS6 in complex with REGN7999 Fab and REGN8023 Fab -

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Basic information

Entry
Database: PDB / ID: 9nrc
TitleTMPRSS6 in complex with REGN7999 Fab and REGN8023 Fab
Components
  • (REGN7999 Fab ...) x 2
  • (REGN8023 Fab ...) x 2
  • Transmembrane protease serine 6
KeywordsMEMBRANE PROTEIN / Serine protease / Matriptase
Function / homology
Function and homology information


membrane protein proteolysis / self proteolysis / Collagen degradation / collagen catabolic process / Hydrolases; Acting on peptide bonds (peptidases); Serine endopeptidases / extracellular matrix disassembly / negative regulation of BMP signaling pathway / BMP signaling pathway / Degradation of the extracellular matrix / metalloendopeptidase activity ...membrane protein proteolysis / self proteolysis / Collagen degradation / collagen catabolic process / Hydrolases; Acting on peptide bonds (peptidases); Serine endopeptidases / extracellular matrix disassembly / negative regulation of BMP signaling pathway / BMP signaling pathway / Degradation of the extracellular matrix / metalloendopeptidase activity / multicellular organismal-level iron ion homeostasis / intracellular iron ion homeostasis / serine-type endopeptidase activity / negative regulation of DNA-templated transcription / negative regulation of transcription by RNA polymerase II / positive regulation of transcription by RNA polymerase II / extracellular space / plasma membrane
Similarity search - Function
Peptidase S1A, matriptase-2 / SEA domain superfamily / SEA domain profile. / SEA domain / SEA domain / CUB domain / CUB domain profile. / Spermadhesin, CUB domain superfamily / Low-density lipoprotein receptor domain class A / LDL-receptor class A (LDLRA) domain signature. ...Peptidase S1A, matriptase-2 / SEA domain superfamily / SEA domain profile. / SEA domain / SEA domain / CUB domain / CUB domain profile. / Spermadhesin, CUB domain superfamily / Low-density lipoprotein receptor domain class A / LDL-receptor class A (LDLRA) domain signature. / LDL-receptor class A (LDLRA) domain profile. / Low-density lipoprotein receptor domain class A / Low-density lipoprotein (LDL) receptor class A repeat / LDL receptor-like superfamily / Serine proteases, trypsin family, histidine active site / Serine proteases, trypsin family, serine active site / Serine proteases, trypsin family, histidine active site. / Peptidase S1A, chymotrypsin family / Serine proteases, trypsin family, serine active site. / Serine proteases, trypsin domain profile. / Trypsin-like serine protease / Serine proteases, trypsin domain / Trypsin / Peptidase S1, PA clan, chymotrypsin-like fold / Peptidase S1, PA clan
Similarity search - Domain/homology
Transmembrane protease serine 6
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.29 Å
AuthorsSaotome, K. / Franklin, M.C.
Funding support1items
OrganizationGrant numberCountry
Not funded
Citation
Journal: JCI Insight / Year: 2025
Title: A TMPRSS6-inhibiting mAb improves disease in a β-thalassemia mouse model and reduces iron in healthy humans.
Authors: Heinrich E Lob / Nikhil Singh / Kusha Mohammadi / Larisa Ivanova / Beth Crowell / Hyon J Kim / Leah Kravets / Nanditha M Das / Yonaton Ray / Jee Hae Kim / Sylvie Rottey / Emily Labriola- ...Authors: Heinrich E Lob / Nikhil Singh / Kusha Mohammadi / Larisa Ivanova / Beth Crowell / Hyon J Kim / Leah Kravets / Nanditha M Das / Yonaton Ray / Jee Hae Kim / Sylvie Rottey / Emily Labriola-Tompkins / Hazem E Hassan / Lorna Farrelly / Harvey F Chin / Marilena Preda / Leigh Spencer Noakes / Kei Saotome / Matthew Franklin / Marc W Retter / Elif Karayusuf / John J Flanagan / William Olson / Kalyan C Nannuru / Vincent Idone / Michael E Burczynski / Olivier A Harari / Lorah Perlee / Griet Van Lancker / Andrew J Murphy / Aris N Economides / Sarah J Hatsell /
Abstract: β-Thalassemia is a genetic disorder arising from mutations in the β-globin gene, leading to ineffective erythropoiesis and iron overload. Ineffective erythropoiesis, a hallmark of β-thalassemia, ...β-Thalassemia is a genetic disorder arising from mutations in the β-globin gene, leading to ineffective erythropoiesis and iron overload. Ineffective erythropoiesis, a hallmark of β-thalassemia, is an important driver of iron overload, which contributes to liver fibrosis, diabetes, and cardiac disease. Iron homeostasis is regulated by the hormone hepcidin; BMP6/hemojuvelin-mediated (BMP6/HJV-mediated) signaling induces hepatic hepcidin expression via SMAD1/5, with transmembrane serine protease 6 (TMPRSS6) being a negative regulator of HJV. Individuals with loss-of-function mutations in the TMPRSS6 gene show increased circulating hepcidin and iron-refractory iron-deficiency anemia, suggesting that blocking TMPRSS6 may be a viable strategy to elevate hepcidin levels in β-thalassemia. We generated a human mAb (REGN7999) that inhibits TMPRSS6. In an Hbbth3/+ mouse model of β-thalassemia, REGN7999 treatment led to significant reductions in liver iron, reduced ineffective erythropoiesis, and showed improvements in RBC health, running distance during forced exercise, and bone density. In a phase I, doubleblind, randomized, placebo-controlled study in healthy human volunteers (NCT05481333), REGN7999 increased serum hepcidin and reduced serum iron with an acceptable tolerability profile. Our results suggest that, by both reducing iron and improving RBC function, inhibition of TMPRSS6 by REGN7999 may offer a therapy for iron overload and impaired erythropoiesis in β-thalassemia.
#1: Journal: Acta Crystallogr D Struct Biol / Year: 2019
Title: Macromolecular structure determination using X-rays, neutrons and electrons: recent developments in Phenix.
Authors: Dorothee Liebschner / Pavel V Afonine / Matthew L Baker / Gábor Bunkóczi / Vincent B Chen / Tristan I Croll / Bradley Hintze / Li Wei Hung / Swati Jain / Airlie J McCoy / Nigel W Moriarty ...Authors: Dorothee Liebschner / Pavel V Afonine / Matthew L Baker / Gábor Bunkóczi / Vincent B Chen / Tristan I Croll / Bradley Hintze / Li Wei Hung / Swati Jain / Airlie J McCoy / Nigel W Moriarty / Robert D Oeffner / Billy K Poon / Michael G Prisant / Randy J Read / Jane S Richardson / David C Richardson / Massimo D Sammito / Oleg V Sobolev / Duncan H Stockwell / Thomas C Terwilliger / Alexandre G Urzhumtsev / Lizbeth L Videau / Christopher J Williams / Paul D Adams /
Abstract: Diffraction (X-ray, neutron and electron) and electron cryo-microscopy are powerful methods to determine three-dimensional macromolecular structures, which are required to understand biological ...Diffraction (X-ray, neutron and electron) and electron cryo-microscopy are powerful methods to determine three-dimensional macromolecular structures, which are required to understand biological processes and to develop new therapeutics against diseases. The overall structure-solution workflow is similar for these techniques, but nuances exist because the properties of the reduced experimental data are different. Software tools for structure determination should therefore be tailored for each method. Phenix is a comprehensive software package for macromolecular structure determination that handles data from any of these techniques. Tasks performed with Phenix include data-quality assessment, map improvement, model building, the validation/rebuilding/refinement cycle and deposition. Each tool caters to the type of experimental data. The design of Phenix emphasizes the automation of procedures, where possible, to minimize repetitive and time-consuming manual tasks, while default parameters are chosen to encourage best practice. A graphical user interface provides access to many command-line features of Phenix and streamlines the transition between programs, project tracking and re-running of previous tasks.
History
DepositionMar 14, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 9, 2025Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Transmembrane protease serine 6
L: REGN7999 Fab light chain
H: REGN7999 Fab heavy chain
B: REGN8023 Fab light chain
C: REGN8023 Fab heavy chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)185,62514
Polymers183,5685
Non-polymers2,0579
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Antibody , 4 types, 4 molecules LHBC

#2: Antibody REGN7999 Fab light chain


Mass: 23381.912 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: Antibody REGN7999 Fab heavy chain


Mass: 25604.521 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)
#4: Antibody REGN8023 Fab light chain


Mass: 24117.859 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)
#5: Antibody REGN8023 Fab heavy chain


Mass: 25308.553 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)

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Protein / Non-polymers , 2 types, 4 molecules A

#1: Protein Transmembrane protease serine 6 / Matriptase-2


Mass: 85154.820 Da / Num. of mol.: 1 / Mutation: S762A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TMPRSS6, UNQ354/PRO618 / Production host: Cricetulus griseus (Chinese hamster)
References: UniProt: Q8IU80, Hydrolases; Acting on peptide bonds (peptidases); Serine endopeptidases
#8: Chemical ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Ca

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Sugars , 2 types, 6 molecules

#6: 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.: 3
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam 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
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}}LINUCSPDB-CARE
#7: 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.: 3 / Source method: obtained synthetically / 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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Details

Has ligand of interestN
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: TMPRSS6 in complex with REGN7999 Fab and REGN8023 Fab / Type: COMPLEX / Entity ID: #1-#5 / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Cricetulus griseus (Chinese hamster)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2200 nm / Nominal defocus min: 1200 nm
Image recordingElectron dose: 40 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

EM softwareName: PHENIX / Version: 1.21.1_5286 / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.29 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 105142 / Symmetry type: POINT
RefinementCross valid method: NONE
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
Displacement parametersBiso mean: 84.51 Å2
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.002912243
ELECTRON MICROSCOPYf_angle_d0.728216677
ELECTRON MICROSCOPYf_chiral_restr0.05171893
ELECTRON MICROSCOPYf_plane_restr0.00582149
ELECTRON MICROSCOPYf_dihedral_angle_d10.69381895

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