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- PDB-9yrb: Factor XIa in complex with Fab fragment of REGN7508-Cat -

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Basic information

Entry
Database: PDB / ID: 9yrb
TitleFactor XIa in complex with Fab fragment of REGN7508-Cat
Components
  • Coagulation factor XI
  • REGN7508 Fab Heavy Chain
  • REGN7508 Light Chain
KeywordsBLOOD CLOTTING / Coagulation / protease
Function / homology
Function and homology information


coagulation factor XIa / serine-type aminopeptidase activity / Defective F9 activation / positive regulation of fibrinolysis / plasminogen activation / : / serine-type peptidase activity / blood coagulation / heparin binding / serine-type endopeptidase activity ...coagulation factor XIa / serine-type aminopeptidase activity / Defective F9 activation / positive regulation of fibrinolysis / plasminogen activation / : / serine-type peptidase activity / blood coagulation / heparin binding / serine-type endopeptidase activity / : / extracellular exosome / extracellular region / membrane / identical protein binding / plasma membrane
Similarity search - Function
Apple domain. / Apple domain / APPLE domain / PAN/Apple domain profile. / PAN domain / PAN/Apple domain / 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 ...Apple domain. / Apple domain / APPLE domain / PAN/Apple domain profile. / PAN domain / PAN/Apple domain / 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
Coagulation factor XI
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.06 Å
AuthorsSaotome, K. / Franklin, M.C.
Funding support1items
OrganizationGrant numberCountry
Other private
Citation
Journal: Blood / Year: 2026
Title: Anticoagulation with mechanistically distinct FXI/FXIa antibodies amrecibart (REGN9933A2) and cenvacibart (REGN7508Cat).
Authors: Dan Chalothorn / Aaron Paul Kithcart / Ethan Marin / Selin Somersan-Karakaya / KehDih Lai / Frederic Cauwberghs / Jonathan Peter Robert Ackroyd / Kusha Mohammadi / Anju Shrestha / George K ...Authors: Dan Chalothorn / Aaron Paul Kithcart / Ethan Marin / Selin Somersan-Karakaya / KehDih Lai / Frederic Cauwberghs / Jonathan Peter Robert Ackroyd / Kusha Mohammadi / Anju Shrestha / George K Ehrlich / Ashique Rafique / Ishita Chatterjee / Kei Saotome / Matthew C Franklin / Andrew J Murphy / William C Olson / Benjamin A Olenchock / Gary A Herman / David E Gutstein / Andres Sirulnik / George D Yancopoulos / Lori G Morton /
Abstract: Thrombosis is a major contributor to global morbidity and mortality. Current standards of care target the extrinsic and/or common pathways of coagulation, effectively inhibiting thrombosis but also ...Thrombosis is a major contributor to global morbidity and mortality. Current standards of care target the extrinsic and/or common pathways of coagulation, effectively inhibiting thrombosis but also increasing bleeding risk, highlighting the unmet need for additional treatment options. Genetic deficiency in factor XI (FXI), a component of the intrinsic pathway, reduces thrombosis risk without spontaneous bleeding. We generated 2 FXI monoclonal antibodies (mAbs) with distinct profiles to provide new approaches to anticoagulation. Cenvacibart (REGN7508Cat) targets the catalytic domain to completely block FXI activity (induced by FXIIa or FXIa in the intrinsic pathway or thrombin in an intrinsic/common pathway amplification loop), thereby maximizing anticoagulation; amrecibart (REGN9933A2) targets the apple 2 domain of FXI/FXIa to specifically prevent FXI activity induced by FXIIa-delivering perhaps less anticoagulation but with potentially lower bleeding risk. We evaluated the anticoagulant effects of both mAbs in vitro in human/non-human primate plasma, in vivo in non-human primates, and healthy volunteers. Both mAbs inhibited intrinsic pathway-triggered coagulation, assessed by activated partial thromboplastin time (aPTT); cenvacibart exhibited a greater increase in aPTT versus amrecibart or other FXI-targeted inhibitors. Neither amrecibart nor cenvacibart affected the extrinsic pathway, assessed by prothrombin time (PT). In non-human primates, both mAbs prevented thrombosis without increasing bleeding. In first-in-human studies, both mAbs were generally well tolerated and dose-dependently inhibited intrinsic pathway-triggered coagulation, with durable aPTT prolongation without affecting PT. Amrecibart and cenvacibart may offer tailored therapies for patients with different bleeding risk profiles. The trials are registered at www.clinicaltrials.gov as #NCT05102136 and #NCT05603195.
#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
DepositionOct 16, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 24, 2026Provider: repository / Type: Initial release
Revision 1.0Jun 24, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Jun 24, 2026Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Jun 24, 2026Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Jun 24, 2026Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Jun 24, 2026Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
H: REGN7508 Fab Heavy Chain
L: REGN7508 Light Chain
A: Coagulation factor XI
F: REGN7508 Fab Heavy Chain
E: REGN7508 Light Chain
C: Coagulation factor XI
B: Coagulation factor XI
D: Coagulation factor XI
hetero molecules


Theoretical massNumber of molelcules
Total (without water)379,98916
Polymers378,2198
Non-polymers1,7708
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails (eV)
d_1ens_1chain "C"
d_2ens_1chain "A"
d_1ens_2chain "B"
d_2ens_2chain "D"
d_1ens_3chain "L"
d_2ens_3chain "E"
d_1ens_4chain "H"
d_2ens_4chain "F"
d_1ens_5chain "G"
d_2ens_5chain "J"
d_1ens_6chain "M"
d_2ens_6chain "K"

NCS domain segments:
Dom-IDComponent-IDEns-IDBeg auth comp-IDBeg label comp-IDEnd auth comp-IDEnd label comp-IDAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
d_11ens_1GLUGLUARGARGCF1 - 36919 - 387
d_12ens_1NAGNAGNAGNAGCK701
d_21ens_1GLUGLUARGARGAC1 - 36919 - 387
d_22ens_1NAGNAGNAGNAGAI701
d_11ens_2ILEILEGLNGLNBG370 - 605388 - 623
d_21ens_2ILEILEGLNGLNDH370 - 605388 - 623
d_11ens_3ASPASPILEILELB1 - 1061 - 106
d_21ens_3ASPASPILEILEEE1 - 1061 - 106
d_11ens_4GLNGLNSERSERHA1 - 1171 - 117
d_21ens_4GLNGLNSERSERFD1 - 1171 - 117
d_11ens_5NAGNAGNAGNAGAJ702
d_12ens_5NAGNAGNAGNAGBM1801
d_21ens_5NAGNAGNAGNAGCL702
d_22ens_5NAGNAGNAGNAGDO1801
d_11ens_6NAGNAGNAGNAGBN1802
d_21ens_6NAGNAGNAGNAGDP1802

NCS ensembles :
ID
ens_1
ens_2
ens_3
ens_4
ens_5
ens_6

NCS oper:
IDCodeMatrixVector
1given(-0.999999982863, 3.83053813853E-5, -0.000181124648353), (-3.83516462647E-5, -0.999999966641, 0.000255434588164), (-0.000181114857792, 0.000255441530215, 0.999999950974)425.025305181, 424.960788372, -0.020966941932
2given(-0.999999983687, -3.60189745417E-5, -0.000176998860246), (3.59758655712E-5, -0.999999969694, 0.000243552222114), (-0.000177007627383, 0.000243545850454, 0.999999954677)425.040330882, 424.947522137, -0.00935190197987
3given(-1), (-1), (1)424.999, 425.001
4given(-1), (-1), (1)424.999, 425.001
5given(-1), (-1), (1)424.999, 425.001
6given(-1), (-1), (1)424.999, 425.001

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Components

#1: Antibody REGN7508 Fab Heavy Chain


Mass: 25123.197 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Cricetulus griseus (Chinese hamster)
#2: Antibody REGN7508 Light Chain


Mass: 23584.139 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Cricetulus griseus (Chinese hamster)
#3: Protein
Coagulation factor XI / FXI / Plasma thromboplastin antecedent / PTA


Mass: 70201.125 Da / Num. of mol.: 4 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / References: UniProt: P03951, coagulation factor XIa
#4: 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.: 8 / 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
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: Factor XIa in complex with REGN7508 Fab / Type: COMPLEX / Entity ID: #1-#3 / 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: 2400 nm / Nominal defocus min: 1400 nm
Image recordingElectron dose: 40 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

EM software
IDNameVersionCategory
1cryoSPARCparticle selection
2PHENIX1.21.1_5286model refinement
13cryoSPARC3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C2 (2 fold cyclic)
3D reconstructionResolution: 3.06 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 110666 / Symmetry type: POINT
RefinementCross valid method: NONE
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
Displacement parametersBiso mean: 95.41 Å2
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.004813188
ELECTRON MICROSCOPYf_angle_d1.084617866
ELECTRON MICROSCOPYf_chiral_restr0.08761996
ELECTRON MICROSCOPYf_plane_restr0.01042268
ELECTRON MICROSCOPYf_dihedral_angle_d5.15681928
Refine LS restraints NCS
Ens-IDDom-IDAsym-IDAuth asym-IDRefine-IDTypeRms dev position (Å)
ens_1d_2FCELECTRON MICROSCOPYNCS constraints2.12431434504E-10
ens_2d_2GBELECTRON MICROSCOPYNCS constraints2.21599657024E-11
ens_3d_2BLELECTRON MICROSCOPYNCS constraints3.15709829033E-13
ens_4d_2AHELECTRON MICROSCOPYNCS constraints6.6090143272E-13
ens_5d_2JAELECTRON MICROSCOPYNCS constraints8.71061971116E-14
ens_6d_2NBELECTRON MICROSCOPYNCS constraints7.0442604173E-14

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