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- EMDB-35526: Cryo-EM structure of CD38 in complex with FTL004 -

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Basic information

Entry
Database: EMDB / ID: EMD-35526
TitleCryo-EM structure of CD38 in complex with FTL004
Map data
Sample
  • Complex: Cryo-EM structure of CD38 in complex with FTL004
    • Protein or peptide: Light chain
    • Protein or peptide: Heavy chain
    • Protein or peptide: ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase 1
Function / homology
Function and homology information


2'-phospho-ADP-ribosyl cyclase/2'-phospho-cyclic-ADP-ribose transferase / phosphorus-oxygen lyase activity / artery smooth muscle contraction / Nicotinate metabolism / ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase / NAD+ nucleosidase activity / NAD metabolic process / NAD+ nucleotidase, cyclic ADP-ribose generating / negative regulation of bone resorption / response to hydroperoxide ...2'-phospho-ADP-ribosyl cyclase/2'-phospho-cyclic-ADP-ribose transferase / phosphorus-oxygen lyase activity / artery smooth muscle contraction / Nicotinate metabolism / ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase / NAD+ nucleosidase activity / NAD metabolic process / NAD+ nucleotidase, cyclic ADP-ribose generating / negative regulation of bone resorption / response to hydroperoxide / long-term synaptic depression / Hydrolases; Glycosylases; Hydrolysing N-glycosyl compounds / B cell proliferation / response to retinoic acid / positive regulation of B cell proliferation / positive regulation of vasoconstriction / response to interleukin-1 / response to progesterone / female pregnancy / apoptotic signaling pathway / B cell receptor signaling pathway / positive regulation of insulin secretion / negative regulation of neuron projection development / response to estradiol / positive regulation of cytosolic calcium ion concentration / transferase activity / positive regulation of cell growth / basolateral plasma membrane / nuclear membrane / response to hypoxia / response to xenobiotic stimulus / negative regulation of DNA-templated transcription / negative regulation of apoptotic process / positive regulation of DNA-templated transcription / cell surface / signal transduction / extracellular exosome / identical protein binding / membrane / plasma membrane
Similarity search - Function
ADP-ribosyl cyclase (CD38/157) / ADP-ribosyl cyclase
Similarity search - Domain/homology
ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.86 Å
AuthorsYang J / Wang Y / Zhang G
Funding support China, United Kingdom, 11 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)32070049 China
National Natural Science Foundation of China (NSFC)32222040 China
National Natural Science Foundation of China (NSFC)81872907 China
Other government2020YFSY0025
Other government2021YJ0454
Other government2019YFS0003
Ministry of Science and Technology (MoST, China)2021YFA1301900 China
Other government20822041D4057
CAMS Innovation Fund for Medical Sciences (CIFMS)2021-I2M-5-075 United Kingdom
Other government2018ZX09201018-021
Other government2017ZX09302010
CitationJournal: J Hematol Oncol / Year: 2022
Title: FTL004, an anti-CD38 mAb with negligible RBC binding and enhanced pro-apoptotic activity, is a novel candidate for treatments of multiple myeloma and non-Hodgkin lymphoma.
Authors: Guangbing Zhang / Cuiyu Guo / Yan Wang / Xianda Zhang / Shuang Liu / Wen Qu / Chunxia Chen / Lingli Yan / Zhouning Yang / Zhixiong Zhang / Xiaohua Jiang / Xiaofeng Chen / Hong Liu / Qinhuai ...Authors: Guangbing Zhang / Cuiyu Guo / Yan Wang / Xianda Zhang / Shuang Liu / Wen Qu / Chunxia Chen / Lingli Yan / Zhouning Yang / Zhixiong Zhang / Xiaohua Jiang / Xiaofeng Chen / Hong Liu / Qinhuai Lai / Xian Wei / Ying Lu / Shengyan Zhao / Han Deng / Yuxi Wang / Lin Yu / Hongbin Yu / Yu Wu / Zhaoming Su / Pengyu Chen / Ziqing Ren / Meng Yu / Feng Qu / Yong Luo / Lantu Gou / Qing Li / Ying Huang / Fanxin Ma / Jinliang Yang /
Abstract: Anti-CD38 monoclonal antibodies (mAbs), daratumumab, and isatuximab have represented a breakthrough in the treatment of multiple myeloma (MM). Recently, CD38-based mAbs were expected to achieve ...Anti-CD38 monoclonal antibodies (mAbs), daratumumab, and isatuximab have represented a breakthrough in the treatment of multiple myeloma (MM). Recently, CD38-based mAbs were expected to achieve increasing potential beyond MM, which encouraged us to develop new anti-CD38 mAbs to meet clinical needs. In this study, we developed a novel humanized anti-CD38 antibody, FTL004, which exhibited enhanced pro-apoptotic ability and negligible binding to red blood cells (RBCs). FTL004 presented a better ability to induce direct apoptosis independent of Fc-mediated cross-linking against lymphoma and MM cell lines as well as primary myeloma cells derived from MM patients. For instance, FTL004 induced RPMI 8226 cells with 55% early apoptosis cells compared with 20% in the isatuximab-treated group. Of interest, FTL004 showed ignorable binding to CD38 on human RBCs in contrast to tumor cells, even at concentrations up to 30 μg/mL. Furthermore, with an engineered Fc domain, FTL004 displayed stronger antibody-dependent cellular cytotoxicity (ADCC) against CD38+ malignant cells. In vivo MM and non-Hodgkin lymphoma tumor xenograft models showed that FTL004 possessed an effective anti-tumor effect. Cryo-electron microscopy structure resolved two epitope centers of FTL004 on CD38: one of which was unique while the other partly overlapped with that of isatuximab. Taken together, FTL004 distinguishes it from other CD38 targeting mAbs and represents a potential candidate for the treatment of MM and non-Hodgkin lymphoma.
History
DepositionMar 1, 2023-
Header (metadata) releaseMar 29, 2023-
Map releaseMar 29, 2023-
UpdateMar 29, 2023-
Current statusMar 29, 2023Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_35526.png

Downloads & links

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Map

FileDownload / File: emd_35526.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 0.85 Å
Density
Contour LevelBy AUTHOR: 0.126
Minimum - Maximum-0.33595532 - 0.6982935
Average (Standard dev.)3.245541e-05 (±0.01494718)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 272.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_35526_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_35526_half_map_2.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Cryo-EM structure of CD38 in complex with FTL004

EntireName: Cryo-EM structure of CD38 in complex with FTL004
Components
  • Complex: Cryo-EM structure of CD38 in complex with FTL004
    • Protein or peptide: Light chain
    • Protein or peptide: Heavy chain
    • Protein or peptide: ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase 1

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Supramolecule #1: Cryo-EM structure of CD38 in complex with FTL004

SupramoleculeName: Cryo-EM structure of CD38 in complex with FTL004 / type: complex / ID: 1 / Chimera: Yes / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Light chain

MacromoleculeName: Light chain / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 23.929572 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: DIVLTQSPAS LAVSPGQRAT ITCRASESVD NFGITFMHWY QQKPGQPPKL LIYRASNLES GVPARFSGSG SRTDFTLTIN PVEANDTAN YYCQQSSKDP RTFGQGTKLE IKRTVAAPSV FIFPPSDEQL KSGTASVVCL LNNFYPREAK VQWKVDNALQ S GNSQESVT ...String:
DIVLTQSPAS LAVSPGQRAT ITCRASESVD NFGITFMHWY QQKPGQPPKL LIYRASNLES GVPARFSGSG SRTDFTLTIN PVEANDTAN YYCQQSSKDP RTFGQGTKLE IKRTVAAPSV FIFPPSDEQL KSGTASVVCL LNNFYPREAK VQWKVDNALQ S GNSQESVT EQDSKDSTYS LSSTLTLSKA DYEKHKVYAC EVTHQGLSSP VTKSFNRGEC

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Macromolecule #2: Heavy chain

MacromoleculeName: Heavy chain / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 22.81751 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: QVQLVQSGSE LKKPGASVKV SCKASGYTFT DYNVHWIRQA PGQGLEWIGY FYPRNGATHY NQKFTGRAVL SADTSVSTAY LQISSLKAE DTAVYFCARG ETPGTFPYWG QGTLVTVSSA STKGPSVFPL APSSKSTSGG TAALGCLVKD YFPEPVTVSW N SGALTSGV ...String:
QVQLVQSGSE LKKPGASVKV SCKASGYTFT DYNVHWIRQA PGQGLEWIGY FYPRNGATHY NQKFTGRAVL SADTSVSTAY LQISSLKAE DTAVYFCARG ETPGTFPYWG QGTLVTVSSA STKGPSVFPL APSSKSTSGG TAALGCLVKD YFPEPVTVSW N SGALTSGV HTFPAVLQSS GLYSLSSVVT VPSSSLGTQT YICNVNHKPS NTKVDKK

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Macromolecule #3: ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase 1

MacromoleculeName: ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase 1 / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO / EC number: ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 26.834471 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: QQWSGPGTTK RFPETVLARC VKYTEIHPEM RHVDCQSVWD AFKGAFISKH PCNITEEDYQ PLMKLGTQTV PCNKILLWSR IKDLAHQFT QVQRDMFTLE DTLLGYLADD LTWCGEFNTS KINYQSCPDW RKDCSNNPVS VFWKTVSRRF AEAACDVVHV M LNGSRSKI ...String:
QQWSGPGTTK RFPETVLARC VKYTEIHPEM RHVDCQSVWD AFKGAFISKH PCNITEEDYQ PLMKLGTQTV PCNKILLWSR IKDLAHQFT QVQRDMFTLE DTLLGYLADD LTWCGEFNTS KINYQSCPDW RKDCSNNPVS VFWKTVSRRF AEAACDVVHV M LNGSRSKI FDKNSTFGSV EVHNLQPEKV QTLEAWVIHG GREDSRDLCQ DPTIKELESI ISKRNIQFSC KNIY

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.2
GridModel: Quantifoil R1.2/1.3 / Material: COPPER / Mesh: 200
VitrificationCryogen name: ETHANE / Chamber humidity: 100 %

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K2 QUANTUM (4k x 4k) / Detector mode: COUNTING / Average electron dose: 60.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.826 µm / Nominal defocus min: 0.752 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.86 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 34435
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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