Crystal structure of CD27 in complex with a neutralizing noncompeting antibody

Teplyakov, Alexey; Obmolova, Galina; Malia, T.; Gilliland, Gary L.

doi:10.1107/s2053230x17005957

Cited by 10 publications

(11 citation statements)

References 44 publications

(43 reference statements)

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“…Moderate inter-CRD motion was observed when aligning the structures of CD27 from the CD27:CD70 complex and the CD27:Fab complex from the PDB entry 5Tl5 , with a CRD1-CRD2 hinge difference of 3.4 degrees and a CRD2-CRD3 hinge difference of 10.7 degrees ( Fig. 2 B ) ( 29 ). One N-linked glycan distant from the CD70-binding interface is observed on N95 residue within CRD2 of CD27 ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Comparison of CD27:CD70 signaling complex structure with prior crystal structures of CD27 allows interrogation of previously proposed mechanistic models of antagonist molecules. Two crystal structures have been reported with CD27 bound to Fab fragments of inhibitory antibodies ( 29 , 48 ). One antibody, 2191, competes for CD70 binding with the interaction epitope that overlaps with the CD70-binding site on CD27 in our structure ( Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Data were phased by molecular replacement using initial models identified using the SwissModel server ( 57 ). An initial molecular replacement solution was found for the CD70 trimer model derived from PDB entry 2RE9 ( 30 ), and subsequently three copies of CD27 monomer derived from PDB entry 5Tl5 were placed ( 29 ). This phased model was further refined using both PHENIX ( 58 ) and BUSTER ( 56 ).…”

Section: Methodsmentioning

confidence: 99%

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Structural delineation and phase-dependent activation of the costimulatory CD27:CD70 complex

Liu

Maben

Wang

et al. 2021

Journal of Biological Chemistry

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CD27 is a tumor necrosis factor (TNF) receptor, which stimulates lymphocytes and promotes their differentiation upon activation by TNF ligand CD70. Activation of the CD27 receptor provides a costimulatory signal to promote T cell, B cell, and NK cell activity to facilitate antitumor and anti-infection immunity. Aberrant increased and focused expression of CD70 on many tumor cells renders CD70 an attractive therapeutic target for direct tumor killing. However, despite their use as drug targets to treat cancers, the molecular basis and atomic details of CD27 and CD70 interaction remain elusive. Here we report the crystal structure of human CD27 in complex with human CD70. Analysis of our structure shows that CD70 adopts a classical TNF ligand homotrimeric assembly to engage CD27 receptors in a 3:3 stoichiometry. By combining structural and rational mutagenesis data with reported disease-correlated mutations, we identified the key amino acid residues of CD27 and CD70 that control this interaction. We also report increased potency for plate-bound CD70 constructs compared with solution-phase ligand in a functional activity to stimulate T-cells in vitro . These findings offer new mechanistic insight into this critical costimulatory interaction.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Structural delineation and phase-dependent activation of the costimulatory CD27:CD70 complex

Liu

Maben

Wang

et al. 2021

Journal of Biological Chemistry

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“…Thirty-three patients from 19 families were diagnosed with CD27 deficiency, while CD70 mutations were detected in 16 patients from 10 families (Table 1). are detrimental to the tertiary structure of CD27, whereas the remainder of the mutations impair the CD27-CD70 protein interaction 32 .…”

Section: Demographic Characteristics Of Patients With Inborn Errors In Cd27 or Cd70mentioning

confidence: 99%

Extended clinical and immunological phenotype and transplant outcome in CD27 and CD70 deficiency

Ghosh¹,

Bal²,

Edwards³

et al. 2020

Blood

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Biallelic mutations in the genes encoding CD27 or its ligand CD70 underlie inborn errors of immunity characterized predominantly by EBV-associated immune dysregulation, such as chronic viremia, severe infectious mononucleosis, hemophagocytic lymphohistiocytosis (HLH), lymphoproliferation and malignancy. A comprehensive understanding of the natural history, immune characteristics and transplant outcomes has remained elusive. Here, in a multi-institutional global collaboration, we collected clinical information of 49 patients from 29 families (CD27 n=33, CD70 n=16), including 24 previously unreported individuals and identified a total of 16 distinct mutations in CD27, and 8 in CD70, respectively. The majority (90%) of patients were EBV+ at diagnosis, but only ~30% presented with infectious mononucleosis. Lymphoproliferation and lymphoma were the main clinical manifestations (70% and 43%, respectively), and 9 of the CD27-deficient patients developed HLH. Twenty-one (43%) patients developed autoinflammatory features including uveitis, arthritis and periodic fever. Detailed immunological characterization revealed aberrant generation of memory B and T cells, including a paucity of EBV-specific T cells, and impaired effector function of CD8+ T cells, thereby providing mechanistic insight into cellular defects underpinning the clinical features of disrupted CD27/CD70 signaling. Nineteen patients underwent allogeneic hematopoietic stem cell transplantation (HSCT) prior to adulthood predominantly because of lymphoma, with 95% survival without disease recurrence. Our data highlight the marked predisposition to lymphoma of both CD27- and CD70-deficient patients. The excellent outcome after HSCT supports the timely implementation of this treatment modality particularly in patients presenting with malignant transformation to lymphoma.

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“…Meanwhile, those false positive of discrete candidates predicted by SEPPA 2.0 can be successfully adjusted through the algorithm of SEPPA 3.0. Besides the case of HIV-1 gp120, another example was also illustrated (Supplementary Figure S4) based on human glycoprotein antigens of CD27 (PDB ID: 5TLK Chain: X), which is an important antibody drug targets for autoimmune diseases and cancers (25). Model performance of 130 individual structures from testing dataset can be found in Supplementary Tables S3 and S4.…”

Section: Resultsmentioning

confidence: 99%

SEPPA 3.0—enhanced spatial epitope prediction enabling glycoprotein antigens

Zhou

Chen

Zhang

et al. 2019

Nucleic Acids Research

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B-cell epitope information is critical to immune therapy and vaccine design. Protein epitopes can be significantly affected by glycosylation, while no methods have considered this till now. Based on previous versions of Spatial Epitope Prediction of Protein Antigens (SEPPA), we here present an enhanced tool SEPPA 3.0, enabling glycoprotein antigens. Parameters were updated based on the latest and largest dataset. Then, additional micro-environmental features of glycosylation triangles and glycosylation-related amino acid indexes were added as important classifiers, coupled with final calibration based on neighboring antigenicity. Logistic regression model was retained as SEPPA 2.0. The AUC value of 0.794 was obtained through 10-fold cross-validation on internal validation. Independent testing on general protein antigens resulted in AUC of 0.740 with BA (balanced accuracy) of 0.657 as baseline of SEPPA 3.0. Most importantly, when tested on independent glycoprotein antigens only, SEPPA 3.0 gave an AUC of 0.749 and BA of 0.665, leading the top performance among peers. As the first server enabling accurate epitope prediction for glycoproteins, SEPPA 3.0 shows significant advantages over popular peers on both general protein and glycoprotein antigens. It can be accessed at http://bidd2.nus.edu.sg/SEPPA3/ or at http://www.badd-cao.net/seppa3/index.html. Batch query is supported.

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Crystal structure of CD27 in complex with a neutralizing noncompeting antibody

Cited by 10 publications

References 44 publications

Structural delineation and phase-dependent activation of the costimulatory CD27:CD70 complex

Structural delineation and phase-dependent activation of the costimulatory CD27:CD70 complex

Extended clinical and immunological phenotype and transplant outcome in CD27 and CD70 deficiency

SEPPA 3.0—enhanced spatial epitope prediction enabling glycoprotein antigens

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