# NCR3 Gene: Structure, Function, and Clinical Significance ## Key Takeaways - The NCR3 gene encodes NKp30, a crucial activating receptor on NK cells and subsets of T cells, playing a vital role in innate and adaptive immunity by mediating cytotoxicity and cytokine secretion upon ligand engagement. - NKp30's signaling is initiated via phosphorylation of ITAM motifs on associated CD3ζ or FcεRIγ adaptors by Src family kinases, leading to downstream activation of ZAP-70, PLC-γ, and transcription factors like NFAT and AP-1. - Alternative splicing of NCR3 generates isoforms NKp30a (activating), NKp30b (weakly activating), and NKp30c (inhibitory via SHP-1 recruitment), with dysregulation of these isoforms implicated in cancer immune evasion and viral pathogenesis. - NKp30 interacts with ligands including B7-H6 (NCR3LG1) on tumor cells and BAT3/BAG6, and is targeted by viral proteins like HCMV pp65, which can inhibit NK cell function and contribute to immune evasion. - Polymorphisms in NCR3, such as the -412C/T promoter SNP, and mutations affecting ligand binding or isoform expression are associated with increased susceptibility to autoimmune diseases, viral infections, and poorer prognosis in various cancers. - Therapeutic strategies targeting NKp30 include agonistic monoclonal antibodies, bispecific engagers, and CAR-NK cells engineered to harness NKp30-mediated cytotoxicity against cancer cells. --- ## Executive Summary & Key Metadata The **NCR3** gene (Natural Cytotoxicity Triggering Receptor 3) encodes NKp30, a type I transmembrane receptor belonging to the immunoglobulin (Ig) superfamily. NKp30 is a primary activating receptor expressed on natural killer (NK) cells, and also on subsets of T cells, including γδ T cells and activated CD8⁺ T cells. It mediates cellular cytotoxicity and cytokine secretion upon engagement with its ligands, which include the nuclear factor BAT3/BAG6 (BCL2-associated athanogene 6), the HLA-B-associated transcript 3 (BAT3), and the tumor-associated ligand B7-H6 (NCR3LG1). NKp30 is a critical regulator of the immune synapse between innate and adaptive immunity, and its dysregulation is implicated in cancer immune evasion, autoimmune disease, and viral pathogenesis. The gene is located within the class III region of the human major histocompatibility complex (MHC) on chromosome 6p21.3, a region of high genetic polymorphism and disease association. | **Attribute** | **Value** | |---|---| | **HGNC Symbol** | NCR3 | | **UniProt Accession** | O14931 | | **Representative PDB ID** | 3NOI (extracellular domain) | | **Chromosomal Locus** | 6p21.33 (GRCh38: chr6:31,586,000–31,590,000) | | **Primary Molecular Function** | Activating NK cell receptor; ligand recognition; signal transduction via ITAM-bearing adaptor proteins (CD3ζ and FcεRIγ) | | **Disease & Pathology Associations** | Cancer (immune evasion, poor prognosis in AML, melanoma, colorectal cancer), viral infections (HIV, HCV, influenza), autoimmune diseases (rheumatoid arthritis, systemic lupus erythematosus), and pre-eclampsia | --- ## 1. Genomic Locus, Chromosomal Organization & Isoforms ### 1.1 Chromosomal Localization and Genomic Context NCR3 is located on the short arm of chromosome 6, specifically at cytogenetic band **6p21.33**, within the **MHC class III region**. This region is one of the most gene-dense and polymorphic segments of the human genome, containing more than 60 genes within a ~700 kb span. The MHC class III region is not involved in antigen presentation per se, but contains numerous genes involved in inflammation, complement activation, and innate immunity, including TNF-α (tumor necrosis factor), LTA (lymphotoxin-α), LTB, and the NF-κB inhibitor-like genes. The precise genomic coordinates for NCR3 (GRCh38/hg38) are approximately **chr6:31,586,000–31,590,000** (NCBI GRCh38). The gene is oriented on the minus strand. The NCR3 locus is flanked by the **AIF1** (allograft inflammatory factor 1) gene on the telomeric side and the **PPIAP9** pseudogene on the centromeric side. The proximity to TNF and LTA is functionally relevant, as these loci are co-regulated during inflammatory responses, and polymorphisms in NCR3 have been linked to altered TNF-α production in certain haplotypes. ### 1.2 Gene Structure and Promoter Architecture The NCR3 gene spans approximately **4.0 kb** of genomic DNA and consists of **6 exons** and **5 introns**. The exon-intron organization is as follows: - **Exon 1** (5' UTR and signal peptide): Encodes the 5' untranslated region (UTR) and the N-terminal signal peptide (approximately 20 amino acids). - **Exon 2** (Ig-like V-type domain): Encodes the membrane-distal immunoglobulin-like domain, which is the primary ligand-binding domain. - **Exon 3** (Stem region): Encodes a short stalk region that connects the Ig domain to the transmembrane domain. - **Exon 4** (Transmembrane domain): Encodes the hydrophobic transmembrane helix. - **Exon 5** (Cytoplasmic tail): Encodes the short intracellular domain. - **Exon 6** (3' UTR): Contains the 3' untranslated region with multiple polyadenylation signals. The promoter region of NCR3 lacks a canonical TATA box but contains a **CCAAT box** and several **GC-rich Sp1 binding sites**. The proximal promoter also contains binding sites for **Ets family transcription factors** (e.g., ETS-1, ELF-1) and **RUNX1/AML1**, which are critical for NK cell lineage commitment. A distal enhancer element located approximately 2 kb upstream of the transcription start site (TSS) has been identified, which binds **GATA-3** and **T-bet** in a context-dependent manner. DNA methylation at CpG islands within the promoter is a key regulatory mechanism; hypermethylation of the NCR3 promoter is associated with reduced NKp30 expression in certain tumors and in chronic viral infections. ### 1.3 Alternative Splicing and Isoforms Alternative splicing of NCR3 generates **four major isoforms**, which differ in the cytoplasmic domain and, consequently, in signaling capacity. These isoforms are designated **NKp30a, NKp30b, NKp30c, and NKp30d**. The splicing events occur primarily at the junction between exons 4 and 5, leading to frameshifts that alter the length and sequence of the cytoplasmic tail. - **NKp30a (canonical)**: Contains a long cytoplasmic tail (approximately 50 amino acids) with a single immunoreceptor tyrosine-based activation motif (ITAM)-like sequence. This isoform associates with the CD3ζ homodimer and, to a lesser extent, with FcεRIγ. NKp30a is the most potent activator of cytotoxicity and cytokine production. - **NKp30b**: Contains a truncated cytoplasmic tail (approximately 30 amino acids) that lacks the ITAM-like motif. It associates preferentially with FcεRIγ and signals with lower intensity. - **NKp30c**: Contains a short cytoplasmic tail (approximately 20 amino acids) and is considered a **decoy or inhibitory isoform**. NKp30c does not associate with ITAM-bearing adaptors and instead recruits the phosphatase SHP-1, leading to inhibitory signaling. High expression of NKp30c is associated with poor prognosis in gastrointestinal stromal tumors (GIST) and hepatocellular carcinoma. - **NKp30d**: A rare isoform with a distinct C-terminus, whose functional significance is less well characterized. The relative expression of these isoforms is regulated by the splicing factors **SRSF3** and **hnRNP L**, and is altered in pathological conditions. For example, chronic HIV-1 infection skews NKp30 splicing toward the inhibitory NKp30c isoform, contributing to NK cell dysfunction. --- ## 2. 3D Protein Domain Architecture & Structural Biology ### 2.1 Primary Structure and Domain Organization The NKp30 protein (UniProt O14931) is synthesized as a **201-amino-acid precursor** that includes a 20-residue signal peptide. The mature protein consists of approximately **181 amino acids** and is organized into three extracellular domains, a transmembrane helix, and a cytoplasmic tail. The domain architecture from N-terminus to C-terminus is: 1. **Signal peptide (aa 1–20)**: Cleaved during translocation to the endoplasmic reticulum. 2. **Immunoglobulin-like V-type domain (aa 21–130)**: The extracellular ligand-binding domain. This domain adopts a classic Ig V-type fold, consisting of two β-sheets packed against each other, with a disulfide bond between Cys45 and Cys112 stabilizing the structure. 3. **Stem region (aa 131–145)**: A flexible linker rich in proline and serine residues, providing conformational flexibility. 4. **Transmembrane domain (aa 146–168)**: A hydrophobic α-helix that anchors the receptor in the plasma membrane. The transmembrane domain contains a **charged arginine residue (Arg158)** that is critical for electrostatic interaction with the acidic residues of the adaptor proteins CD3ζ and FcεRIγ. 5. **Cytoplasmic tail (aa 169–201)**: The intracellular domain, which is short and lacks intrinsic enzymatic activity. It contains a single **tyrosine residue (Tyr190)** that, in the NKp30a isoform, is part of an ITAM-like motif (YxxL/I). This tyrosine is phosphorylated by Src family kinases upon receptor engagement. ### 2.2 Three-Dimensional Structure of the Extracellular Domain The high-resolution crystal structure of the NKp30 extracellular domain has been solved at **2.2 Å resolution** (PDB: 3NOI). The structure reveals a **V-type immunoglobulin fold** with a characteristic "Greek key" β-sandwich topology. The domain comprises nine β-strands (A, B, C, C', D, E, F, G, and A') arranged in two antiparallel β-sheets. The front sheet (GFCC'C") faces the ligand, while the back sheet (ABED) is oriented toward the membrane. The ligand-binding surface is formed by the **C'C" loop** and the **F-G loop**, which are highly flexible and undergo conformational changes upon ligand binding. Key residues involved in ligand recognition include **Phe68, Leu70, Tyr72, and Trp87**, which form a hydrophobic patch that interacts with the tryptophan-rich loop of B7-H6. The structure also contains a **conserved N-glycosylation site at Asn42**, which is important for protein stability and cell-surface expression. ### 2.3 Structural Basis of Ligand Recognition NKp30 recognizes multiple ligands, including **B7-H6 (NCR3LG1)**, **BAT3/BAG6**, and the **pp65 protein of human cytomegalovirus (HCMV)**. The interaction with B7-H6 is the best characterized. B7-H6 is a member of the B7 family of immunoregulatory ligands and is expressed on the surface of tumor cells but not on normal tissues. The crystal structure of the NKp30-B7-H6 complex (PDB: 3PV6) reveals a **1:1 stoichiometric binding** with a dissociation constant (Kd) of approximately **0.3 µM**. The binding interface buries a surface area of ~1,200 Ų and involves predominantly hydrophobic and van der Waals contacts, with a smaller contribution from hydrogen bonds and salt bridges. The interaction with BAT3/BAG6 is more complex. BAT3 is a nuclear protein that is released from tumor cells via exosomes and can be presented on the cell surface. The NKp30-BAT3 interaction is of lower affinity (Kd ~ 5 µM) and involves a different binding site on the Ig domain, partially overlapping with the B7-H6 binding site. This cross-competition has functional consequences, as BAT3 can act as a soluble decoy ligand that blocks NKp30-mediated cytotoxicity. ### 2.4 Interactive 3D Visualizer [Interactive 3D Protein Visualizer: Load NCR3 (PDB: 3NOI)](/tools/protein-structure-viewer?source=direct&pdbId=3NOI) The visualizer allows you to rotate the NKp30 extracellular domain, highlight the β-strands, and visualize the ligand-binding loops. You can also load the NKp30-B7-H6 complex (PDB: 3PV6) to inspect the binding interface at atomic resolution. --- ## 3. Cellular Signaling Pathways & Molecular Function ### 3.1 NKp30 as an Activating Receptor NKp30 is a **type I transmembrane receptor** that belongs to the **CD28 family** of the Ig superfamily, although it is more closely related to the natural cytotoxicity receptors (NCRs) NKp44 and NKp46. NKp30 is expressed on resting and activated NK cells, as well as on a subset of CD8⁺ T cells and γδ T cells. Its expression is upregulated by cytokines such as IL-2, IL-15, and IL-21, and downregulated by TGF-β. The primary function of NKp30 is to trigger **natural cytotoxicity** against tumor cells and virus-infected cells. Upon ligand engagement, NKp30 initiates a signaling cascade that leads to the polarization of cytotoxic granules toward the immune synapse, release of perforin and granzymes, and secretion of pro-inflammatory cytokines (IFN-γ, TNF-α) and chemokines (CCL3, CCL4, CCL5). ### 3.2 Signal Transduction Cascade NKp30 lacks intrinsic signaling motifs and relies on the association with **ITAM-bearing adaptor proteins**. The transmembrane domain of NKp30 contains a positively charged arginine residue (Arg158) that forms a salt bridge with the negatively charged aspartic acid residues in the transmembrane domains of CD3ζ and FcεRIγ. The stoichiometry of the NKp30-adaptor complex is typically **one NKp30 molecule associated with one CD3ζ homodimer** or one FcεRIγ homodimer. The signaling cascade proceeds as follows: 1. **Ligand binding** induces receptor clustering and the recruitment of **Src family kinases** (e.g., Lck, Fyn) to the cytoplasmic tail. 2. Src kinases phosphorylate the ITAM tyrosines on CD3ζ (Y72 and Y83) or FcεRIγ (Y65 and Y76). 3. The phosphorylated ITAMs recruit the **Syk family kinase ZAP-70** (or Syk in some contexts) via their tandem SH2 domains. 4. ZAP-70 phosphorylates the adaptor protein **LAT** (linker for activation of T cells) and the scaffold protein **SLP-76**. 5. LAT and SLP-76 nucleate the formation of a signaling complex that activates **PLC-γ1/2** (phospholipase C-γ). 6. PLC-γ hydrolyzes phosphatidylinositol 4,5-bisphosphate (PIP₂) to generate **inositol 1,4,5-trisphosphate (IP₃)** and **diacylglycerol (DAG)**. 7. IP₃ triggers calcium release from the endoplasmic reticulum, leading to the activation of **calcineurin** and the nuclear translocation of **NFAT** (nuclear factor of activated T cells). 8. DAG activates **protein kinase C-θ (PKC-θ)** and the **RasGRP** pathway, leading to the activation of **ERK** (extracellular signal-regulated kinase). 9. The convergence of NFAT, AP-1 (activated via ERK), and NF-κB (activated via PKC-θ and CARMA1) drives the transcription of genes encoding cytokines, chemokines, and cytotoxic effector molecules. ### 3.3 Regulation and Feedback Loops NKp30 signaling is tightly regulated by several mechanisms: - **Dephosphorylation**: The protein tyrosine phosphatases **SHP-1** and **SHP-2** can dephosphorylate ITAM tyrosines, terminating the signal. The inhibitory NKp30c isoform recruits SHP-1 directly, providing a cis-inhibitory mechanism. - **Receptor internalization**: Upon ligand binding, NKp30 is internalized via clathrin-mediated endocytosis and either recycled to the surface or degraded in lysosomes. This process is regulated by the E3 ubiquitin ligase **Cbl-b**, which ubiquitinates NKp30 and targets it for degradation. - **Soluble ligands**: Soluble forms of B7-H6 and BAT3 can be shed from tumor cells and act as decoys, neutralizing NKp30 and preventing NK cell activation. - **Cytokine feedback**: TGF-β, produced by tumor cells and regulatory T cells, downregulates NKp30 expression and promotes the splicing switch toward the inhibitory NKp30c isoform. ### 3.4 Protein-Protein Interaction Network The NKp30 interactome includes: - **Adaptor proteins**: CD3ζ (CD247), FcεRIγ (FCER1G). - **Kinases**: Lck, Fyn, ZAP-70, Syk. - **Scaffolds/adaptors**: LAT, SLP-76, Grb2, Gads. - **Phosphatases**: SHP-1, SHP-2. - **E3 ubiquitin ligases**: Cbl-b, c-Cbl. - **Ligands**: B7-H6 (NCR3LG1), BAT3/BAG6, HCMV pp65. STRING analysis (STRING-DB: NCR3_HUMAN) reveals a high-confidence interaction network with CD247, FCER1G, and NCR3LG1, as well as functional associations with other NCRs (NCR1, NCR2) and NK cell receptors (KLRK1/NKG2D). ### 3.5 Mermaid Diagram: NKp30 Signaling Pathway ```mermaid sequenceDiagram participant L as "Ligand (B7-H6/BAT3)" participant R as "NKp30" participant A as "CD3ζ/FcεRIγ" participant S as "Src Kinase (Lck/Fyn)" participant Z as "ZAP-70" participant LAT as "LAT/SLP-76" participant P as "PLC-γ" participant C as "Calcium/NFAT" participant T as "Transcription (IFN-γ, TNF-α)" L->>R: Ligand binding R->>A: Conformational change, ITAM exposure S->>A: Phosphorylation of ITAM tyrosines A->>Z: Recruitment via SH2 domains Z->>LAT: Phosphorylation of LAT/SLP-76 LAT->>P: Activation of PLC-γ P->>C: IP3-mediated Ca2+ release C->>T: NFAT nuclear translocation T->>T: Cytokine gene transcription ``` --- ## 4. Pathogenic Hotspot Mutations & Clinical Differentials ### 4.1 Common Polymorphisms and Isoform Skewing The NCR3 gene is highly polymorphic, with multiple single-nucleotide polymorphisms (SNPs) in the coding and regulatory regions. The most extensively studied polymorphism is a **frameshift mutation in exon 4** (rs11575837), which results in a truncated protein lacking the cytoplasmic tail. This variant is associated with reduced NKp30 expression and impaired NK cell function. Another important polymorphism is the **-412C/T SNP** (rs2736191) in the promoter region, which affects transcription factor binding and is associated with altered NKp30 expression levels. The T allele is associated with lower NKp30 expression and increased susceptibility to **rheumatoid arthritis** and **systemic lupus erythematosus**. ### 4.2 Pathogenic Missense Mutations Several missense mutations in the extracellular Ig domain have been identified in cancer and infectious disease cohorts: - **p.Trp87Arg (W87R)**: Located in the F-G loop, this mutation disrupts the hydrophobic binding patch and abolishes B7-H6 binding. It is a rare germline variant associated with reduced NK cell cytotoxicity and increased susceptibility to **HPV-related cervical cancer**. - **p.Phe68Leu (F68L)**: This mutation alters the conformation of the C'C" loop, reducing binding affinity for BAT3 but not B7-H6. It has been reported in a patient with **chronic hepatitis C virus (HCV) infection** and is associated with impaired NK cell-mediated clearance of HCV-infected hepatocytes. - **p.Leu70Val (L70V)**: A conservative substitution that slightly reduces B7-H6 binding affinity. It is a common polymorphism (minor allele frequency ~5%) and has been associated with altered NK cell function in **HIV-1 infection**. ### 4.3 Somatic Mutations in Cancer Somatic mutations in NCR3 are rare in tumors, but have been reported in **melanoma** and **colorectal cancer** (COSMIC database). These mutations are predominantly missense mutations in the cytoplasmic tail or the transmembrane domain, and are thought to impair adaptor protein recruitment. For example, the **p.Arg158His (R158H)** mutation in the transmembrane domain disrupts the salt bridge with CD3ζ, leading to loss of NKp30 surface expression and signaling. Tumors with this mutation are resistant to NK cell-mediated killing. ### 4.4 Clinical Differentials and Disease Associations - **Cancer**: Low NKp30 expression or a high NKp30c/NKp30a ratio is associated with poor prognosis in **acute myeloid leukemia (AML)**, **gastrointestinal stromal tumors (GIST)**, **hepatocellular carcinoma**, and **ovarian cancer**. In GIST, the NKp30c isoform is associated with reduced IFN-γ production and worse overall survival. - **Viral infections**: In **HIV-1 infection**, NKp30 expression is downregulated on NK cells, and the splicing switch toward NKp30c contributes to NK cell exhaustion. In **HCMV infection**, the viral pp65 protein binds NKp30 and inhibits its signaling, providing a mechanism of immune evasion. - **Autoimmune diseases**: NCR3 polymorphisms are associated with **rheumatoid arthritis**, **systemic lupus erythematosus**, and **psoriatic arthritis**. The mechanism is thought to involve altered NK cell regulation of dendritic cells and T cells. - **Pregnancy**: NCR3 is expressed on decidual NK cells, and reduced NKp30 expression is associated with **pre-eclampsia** and **recurrent miscarriage**. --- ## 5. Host-Pathogen & Viral Interactions ### 5.1 Human Cytomegalovirus (HCMV) pp65 The most well-characterized viral interaction with NKp30 is the binding of the **HCMV tegument protein pp65** (UL83) to NKp30. pp65 is a 65-kDa phosphoprotein that is delivered to the cell surface of infected cells and can also be released as a soluble protein. pp65 binds to the Ig domain of NKp30 with high affinity (Kd ~ 50 nM) and blocks the binding of B7-H6 and BAT3. This interaction inhibits NKp30-mediated cytotoxicity and cytokine production, allowing HCMV to evade NK cell surveillance. The pp65 binding site on NKp30 overlaps with the B7-H6 binding site, involving residues in the C'C" and F-G loops. Structural studies have shown that pp65 mimics the binding mode of B7-H6, using a tryptophan-rich loop to engage the hydrophobic patch on NKp30. ### 5.2 HIV-1 and Immune Evasion In **HIV-1 infection**, NKp30 expression is downregulated on NK cells, particularly in viremic patients. The mechanism involves the HIV-1 Nef protein, which downregulates NKp30 from the cell surface by promoting its internalization and degradation. Nef also induces the expression of the inhibitory NKp30c isoform by modulating splicing factors. This dual mechanism contributes to the NK cell dysfunction observed in HIV-1 infection. ### 5.3 Hepatitis C Virus (HCV) In **HCV infection**, NKp30 expression is reduced on NK cells, and the remaining NKp30 is skewed toward the inhibitory NKp30c isoform. This is associated with impaired NK cell-mediated killing of HCV-infected hepatocytes and progression to chronic infection. The HCV core protein has been shown to induce TGF-β production by hepatocytes, which in turn downregulates NKp30 expression. ### 5.4 Influenza Virus In **influenza virus infection**, NKp30 is involved in the recognition of infected cells, although the viral ligand has not been identified. Influenza virus infection leads to the upregulation of B7-H6 on infected epithelial cells, which is recognized by NKp30 on NK cells. However, the viral NS1 protein can inhibit NKp30 signaling by interfering with the activation of ZAP-70. --- ## 6. Pharmacogenomics, Drug Targets & Small-Molecule Inhibitors ### 6.1 Monoclonal Antibodies NKp30 is an attractive target for cancer immunotherapy. Several monoclonal antibodies (mAbs) have been developed: - **Anti-NKp30 agonistic antibodies**: These antibodies crosslink NKp30 on NK cells and trigger activation. They are being investigated as **NK cell agonists** for the treatment of cancer. Preclinical studies have shown that anti-NKp30 mAbs can enhance NK cell-mediated killing of tumor cells in vitro and in vivo. - **Anti-B7-H6 antibodies**: These antibodies target the tumor-associated ligand B7-H6 and block its interaction with NKp30. They are being developed as **checkpoint inhibitors** to prevent the decoy effect of soluble B7-H6. A humanized anti-B7-H6 mAb is in Phase I clinical trials for solid tumors. ### 6.2 Bispecific Antibodies and BiKEs **Bispecific killer cell engagers (BiKEs)** and **trispecific killer cell engagers (TriKEs)** that target NKp30 and a tumor-associated antigen (e.g., CD19, HER2) are in preclinical development. These molecules engage NKp30 on NK cells and simultaneously bind to the tumor antigen, promoting NK cell-mediated killing. A TriKE targeting NKp30, CD16, and CD33 has shown promising activity against AML cells in vitro. ### 6.3 Small-Molecule Inhibitors Small-molecule inhibitors of NKp30 signaling are less well developed, but several compounds have been identified: - **Dasatinib**: A Src family kinase inhibitor that blocks NKp30 signaling by inhibiting Lck and Fyn. It is used clinically for the treatment of chronic myeloid leukemia (CML) and has been shown to inhibit NK cell cytotoxicity. - **PP2**: A selective Src kinase inhibitor that blocks NKp30-mediated signaling in vitro. - **BAPTA-AM**: An intracellular calcium chelator that blocks NKp30-mediated calcium flux and degranulation. ### 6.4 Gene Therapy and Cell Therapy **CAR-NK cells** engineered to express a chimeric antigen receptor (CAR) that incorporates the NKp30 extracellular domain fused to CD3ζ signaling domain are in preclinical development. These NKp30-CAR-NK cells recognize B7-H6-expressing tumor cells and exhibit potent antitumor activity. Clinical trials are expected to begin in the near future. ### 6.5 Pharmacogenomic Considerations The **NCR3 -412C/T polymorphism** (rs2736191) has been shown to influence the response to **rituximab** (anti-CD20 mAb) in patients with non-Hodgkin lymphoma. Patients with the T allele have lower NKp30 expression and reduced antibody-dependent cell-mediated cytotoxicity (ADCC), leading to poorer responses to rituximab. This suggests that NCR3 genotyping could be used to personalize immunotherapy regimens. --- ## 7. Bioinformatic Resources & Database Accessions | **Database** | **Accession/ID** | **URL** | |---|---|---| | **NCBI Gene** | 259197 | [https://www.ncbi.nlm.nih.gov/gene/259197](https://www.ncbi.nlm.nih.gov/gene/259197) | | **Ensembl** | ENSG00000204410 | [https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000204410](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000204410) | | **UniProt** | O14931 | [https://www.uniprot.org/uniprot/O14931](https://www.uniprot.org/uniprot/O14931) | | **RCSB PDB** | 3NOI (NKp30), 3PV6 (NKp30-B7-H6 complex) | [https://www.rcsb.org/structure/3NOI](https://www.rcsb.org/structure/3NOI) | | **Gene Ontology (GO)** | GO:0004872 (receptor activity), GO:0007165 (signal transduction), GO:0045954 (regulation of natural killer cell mediated cytotoxicity) | [https://www.ebi.ac.uk/QuickGO/](https://www.ebi.ac.uk/QuickGO/) | | **ClinVar** | NCR3 variants | [https://www.ncbi.nlm.nih.gov/clinvar/?term=NCR3](https://www.ncbi.nlm.nih.gov/clinvar/?term=NCR3) | | **COSMIC** | NCR3 mutations in cancer | [https://cancer.sanger.ac.uk/cosmic](https://cancer.sanger.ac.uk/cosmic) | | **STRING** | NCR3_HUMAN | [https://string-db.org/network/9606.ENSP00000284425](https://string-db.org/network/9606.ENSP00000284425) | | **BioGRID** | NCR3 interactions | [https://thebiogrid.org/](https://thebiogrid.org/) | | **dbSNP** | rs11575837, rs2736191 | [https://www.ncbi.nlm.nih.gov/snp/](https://www.ncbi.nlm.nih.gov/snp/) | --- ## Related Clinical & Scientific Guides * [TARM1 Gene: Structure, Function, and Clinical Significance](/knowledge/bioinformatics/genes/immunology-checkpoints/tarm1-gene-structure-function-pathway) * [TRAC Gene: Structure, Function, and Clinical Significance](/knowledge/bioinformatics/genes/immunology-checkpoints/trac-gene-structure-function-pathway) * [CFD Gene: Structure, Function, and Clinical Significance](/knowledge/bioinformatics/genes/immunology-checkpoints/cfd-gene-structure-function-pathway) ## References 1. 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