3hpj

Human Class I MHC HLA-A2 in complex with the WT-1 (126-134) peptide

spinqualitylabelsall models 3hpj, resolution 2.00Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 3hpj is a 6 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: GOL Related: 1tvb, 3myj Gene: HLA-A, HLAA (HUMAN), B2M, CDABP0092, HDCMA22P (HUMAN) Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease [WT1_HUMAN] Defects in WT1 are the cause of Frasier syndrome (FS) [MIM:136680]. FS is characterized by a slowly progressing nephropathy leading to renal failure in adolescence or early adulthood, male pseudohermaphroditism, and no Wilms tumor. As for histological findings of the kidneys, focal glomerular sclerosis is often observed. There is phenotypic overlap with Denys-Drash syndrome. Inheritance is autosomal dominant. Defects in WT1 are the cause of Wilms tumor 1 (WT1) [MIM:194070]. WT is an embryonal malignancy of the kidney that affects approximately 1 in 10'000 infants and young children. It occurs both in sporadic and hereditary forms. Defects in WT1 are the cause of Denys-Drash syndrome (DDS) [MIM:194080]. DDS is a typical nephropathy characterized by diffuse mesangial sclerosis, genital abnormalities, and/or Wilms tumor. There is phenotypic overlap with WAGR syndrome and Frasier syndrome. Inheritance is autosomal dominant, but most cases are sporadic. Defects in WT1 are the cause of nephrotic syndrome type 4 (NPHS4) [MIM:256370]. A renal disease characterized clinically by proteinuria, hypoalbuminemia, hyperlipidemia and edema. Kidney biopsies show non-specific histologic changes such as focal segmental glomerulosclerosis and diffuse mesangial proliferation. Some affected individuals have an inherited steroid-resistant form and progress to end-stage renal failure. Most patients with NPHS4 show diffuse mesangial sclerosis on renal biopsy, which is a pathologic entity characterized by mesangial matrix expansion with no mesangial hypercellularity, hypertrophy of the podocytes, vacuolized podocytes, thickened basement membranes, and diminished patency of the capillary lumen. Defects in WT1 are a cause of Meacham syndrome (MEACHS) [MIM:608978]. Meacham syndrome is a rare sporadically occurring multiple malformation syndrome characterized by male pseudohermaphroditism with abnormal internal female genitalia comprising a uterus and double or septate vagina, complex congenital heart defect and diaphragmatic abnormalities. Note=A chromosomal aberration involving WT1 may be a cause of desmoplastic small round cell tumor (DSRCT). Translocation t(11;22)(p13;q12) with EWSR1. Defects in WT1 may be a cause of mesothelioma malignant (MESOM) [MIM:156240]. An aggressive neoplasm of the serosal lining of the chest. It appears as broad sheets of cells, with some regions containing spindle-shaped, sarcoma-like cells and other regions showing adenomatous patterns. Pleural mesotheliomas have been linked to exposure to asbestos. [B2MG_HUMAN] Defects in B2M are the cause of hypercatabolic hypoproteinemia (HYCATHYP) [MIM:241600]. Affected individuals show marked reduction in serum concentrations of immunoglobulin and albumin, probably due to rapid degradation. Note=Beta-2-microglobulin may adopt the fibrillar configuration of amyloid in certain pathologic states. The capacity to assemble into amyloid fibrils is concentration dependent. Persistently high beta(2)-microglobulin serum levels lead to amyloidosis in patients on long-term hemodialysis. Function [1A02_HUMAN] Involved in the presentation of foreign antigens to the immune system. [WT1_HUMAN] Transcription factor that plays an important role in cellular development and cell survival. Regulates the expression of numerous target genes, including EPO. Plays an essential role for development of the urogenital system. Recognizes and binds to the DNA sequence 5'-CGCCCCCGC-3'. It has a tumor suppressor as well as an oncogenic role in tumor formation. Function may be isoform-specific: isoforms lacking the KTS motif may act as transcription factors. Isoforms containing the KTS motif may bind mRNA and play a role in mRNA metabolism or splicing. Isoform 1 has lower affinity for DNA, and can bind RNA. [B2MG_HUMAN] Component of the class I major histocompatibility complex (MHC). Involved in the presentation of peptide antigens to the immune system. Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMed Presentation of peptides by class I or class II major histocompatibility complex (MHC) molecules is required for the initiation and propagation of a T cell-mediated immune response. Peptides from the Wilms Tumor 1 transcription factor (WT1), upregulated in many hematopoetic and solid tumors, can be recognized by T cells and numerous efforts are underway to engineer WT1-based cancer vaccines. Here we determined the structures of the class I MHC molecule HLA-A*0201 bound to the native 126-134 epitope of the WT1 peptide and a recently described variant (R1Y) with improved MHC binding. The R1Y variant, a potential vaccine candidate, alters the positions of MHC charged side chains near the peptide N-terminus and significantly reduces the peptide/MHC electrostatic surface potential. These alterations indicate that the R1Y variant is an imperfect mimic of the native WT1 peptide, and suggest caution in its use as a therapeutic vaccine. Stability measurements revealed how the R1Y substitution enhances MHC binding affinity, and together with the structures suggest a strategy for engineering WT1 variants with improved MHC binding that retain the structural features of the native peptide/MHC complex. Structures of native and affinity-enhanced WT1 epitopes bound to HLA-A*0201: implications for WT1-based cancer therapeutics.,Borbulevych OY, Do P, Baker BM Mol Immunol. 2010 Sep;47(15):2519-24. Epub 2010 Jul 8. PMID:20619457 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

Proteopedia Page Contributors and Editors (what is this?)

OCA