5ocx

Crystal structure of ACPA E4 in complex with CII-C-13-CIT

spinqualitylabelsall models 5ocx, resolution 1.75Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5ocx is a 3 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.75Å Ligands: CIR, EDO, PCA Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease CO2A1_HUMAN Defects in COL2A1 are the cause of spondyloepiphyseal dysplasia congenital type (SEDC) [MIM:183900. This disorder is characterized by disproportionate short stature and pleiotropic involvement of the skeletal and ocular systems. Defects in COL2A1 are the cause of spondyloepimetaphyseal dysplasia, Strudwick type (SEMDSTWK) [MIM:184250. A bone disease characterized by disproportionate short stature from birth, with a very short trunk and shortened limbs, and skeletal abnormalities including lordosis, scoliosis, flattened vertebrae, pectus carinatum, coxa vara, clubfoot, and abnormal epiphyses or metaphyses. A distinctive radiographic feature is irregular sclerotic changes, described as dappled in the metaphyses of the long bones.[:] Defects in COL2A1 are the cause of achondrogenesis type 2 (ACG2) [MIM:200610; also known as achondrogenesis-hypochondrogenesis type II. ACG2 is a disease characterized by the absence of ossification in the vertebral column, sacrum and pubic bones. Defects in COL2A1 are the cause of Legg-Calve-Perthes disease (LCPD) [MIM:150600; also known as Legg-Perthes disease or Perthes disease. LCPD is characterized by loss of circulation to the femoral head, resulting in avascular necrosis in a growing child. Clinical pictures of the disease vary, depending on the phase of disease progression through ischemia, revascularization, fracture and collapse, and repair and remodeling of the bone. Defects in COL2A1 are the cause of Kniest dysplasia (KD) [MIM:156550; also known as Kniest syndrome or metatropic dwarfism type II. KD is a moderately severe chondrodysplasia phenotype that results from mutations in the COL2A1 gene. Characteristics of the disorder include a short trunk and extremities, mid-face hypoplasia, cleft palate, myopia, retinal detachment, and hearing loss. Defects in COL2A1 are a cause of primary avascular necrosis of femoral head (ANFH) [MIM:608805; also known as ischemic necrosis of the femoral head or osteonecrosis of the femoral head. ANFH causes disability that often requires surgical intervention. Most cases are sporadic, but families in which there is an autosomal dominant inheritance of the disease have been identified. It has been estimated that 300,000 to 600,000 people in the United States have ANFH. Approximately 15,000 new cases of this common and disabling disorder are reported annually. The age at the onset is earlier than that for osteoarthritis. The diagnosis is typically made when patients are between the ages of 30 and 60 years. The clinical manifestations, such as pain on exertion, a limping gait, and a discrepancy in leg length, cause considerable disability. Moreover, nearly 10 percent of the 500,000 total-hip arthroplasties performed each year in the United States involve patients with ANFH. As a result, this disease creates a substantial socioeconomic cost as well as a burden for patients and their families. Defects in COL2A1 are the cause of osteoarthritis with mild chondrodysplasia (OACD) [MIM:604864. Osteoarthritis is a common disease that produces joint pain and stiffness together with radiologic evidence of progressive degeneration of joint cartilage. Some forms of osteoarthritis are secondary to events such as trauma, infections, metabolic disorders, or congenital or heritable conditions that deform the epiphyses or related structures. In most patients, however, there is no readily identifiable cause of osteoarthritis. Inheritance in a Mendelian dominant manner has been demonstrated in some families with primary generalized osteoarthritis. Reports demonstrate coinheritance of primary generalized osteoarthritis with specific alleles of the gene COL2A1, the precursor of the major protein of cartilage. Defects in COL2A1 are the cause of platyspondylic lethal skeletal dysplasia Torrance type (PLSD-T) [MIM:151210. Platyspondylic lethal skeletal dysplasias (PLSDs) are a heterogeneous group of chondrodysplasias characterized by severe platyspondyly and limb shortening. PLSD-T is characterized by varying platyspondyly, short ribs with anterior cupping, hypoplasia of the lower ilia with broad ischial and pubic bones, and shortening of the tubular bones with splayed and cupped metaphyses. Histology of the growth plate typically shows focal hypercellularity with slightly enlarged chondrocytes in the resting cartilage and relatively well-preserved columnar formation and ossification at the chondro-osseous junction. PLSD-T is generally a perinatally lethal disease, but a few long-term survivors have been reported. Defects in COL2A1 are the cause of multiple epiphyseal dysplasia with myopia and conductive deafness (EDMMD) [MIM:132450. Multiple epiphyseal dysplasia is a generalized skeletal dysplasia associated with significant morbidity. Joint pain, joint deformity, waddling gait, and short stature are the main clinical signs and symptoms. EDMMD is an autosomal dominant disorder characterized by epiphyseal dysplasia associated with progressive myopia, retinal thinning, crenated cataracts, conductive deafness. Defects in COL2A1 are the cause of spondyloperipheral dysplasia (SPD) [MIM:271700. SPD patients manifest short stature, midface hypoplasia, sensorineural hearing loss, spondyloepiphyseal dysplasia, platyspondyly and brachydactyly. Defects in COL2A1 are the cause of Stickler syndrome type 1 (STL1) [MIM:108300; also known as vitreous type 1, or membranous vitreous type. STL1 is an autosomal dominant form of Stickler syndrome, an inherited disorder that associates ocular signs with more or less complete forms of Pierre Robin sequence, bone disorders and sensorineural deafness. Ocular disorders may include juvenile cataract, myopia, strabismus, vitreoretinal or chorioretinal degeneration, retinal detachment, and chronic uveitis. Robin sequence includes an opening in the roof of the mouth (a cleft palate), a large tongue (macroglossia), and a small lower jaw (micrognathia). Bones are affected by slight platyspondylisis and large, often defective epiphyses. Juvenile joint laxity is followed by early signs of arthrosis. The degree of hearing loss varies among affected individuals and may become more severe over time. Syndrome expressivity is variable. Defects in COL2A1 are the cause of Stickler syndrome type 1 non-syndromic ocular (STL1O) [MIM:609508. STL1O is an autosomal dominant form of Stickler syndrome characterized by the ocular signs typically seen in STL1 such as cataract, myopia, retinal detachment. STL1 systemic features of premature osteoarthritis, cleft palate, hearing impairment, and craniofacial abnormalities are either absent or very mild in STL1O patients. Defects in COL2A1 are a cause of rhegmatogenous retinal detachment autosomal dominant (DRRD) [MIM:609508. Rhegmatogenous retinal detachment most frequently results from a break or tear in the retina that allows fluid from the vitreous humor to enter the potential space beneath the retina. It is often associated with pathologic myopia and in most cases leads to visual impairment or blindness if untreated. Defects in COL2A1 are the cause of Czech dysplasia (CZECHD) [MIM:609162. A skeletal dysplasia characterized by early-onset, progressive pseudorheumatoid arthritis, platyspondyly, and short third and fourth toes. Function CO2A1_HUMAN Type II collagen is specific for cartilaginous tissues. It is essential for the normal embryonic development of the skeleton, for linear growth and for the ability of cartilage to resist compressive forces. Publication Abstract from PubMed OBJECTIVE: Anti-citrullinated protein antibodies (ACPAs) develop many years before the clinical onset of rheumatoid arthritis (RA). This study was undertaken to address the molecular basis of the specificity and cross-reactivity of ACPAs from patients with RA. METHODS: Antibodies isolated from RA patients were expressed as monoclonal chimeric antibodies with mouse Fc. These antibodies were characterized for glycosylation using mass spectrometry, and their cross-reactivity was assessed using Biacore and Luminex immunoassays. The crystal structures of the antigen-binding fragment (Fab) of the monoclonal ACPA E4 in complex with 3 different citrullinated peptides were determined using x-ray crystallography. The prevalence of autoantibodies reactive against 3 of the citrullinated peptides that also interacted with E4 was investigated by Luminex immunoassay in 2 Swedish cohorts of RA patients. RESULTS: Analysis of the crystal structures of a monoclonal ACPA from human RA serum in complex with citrullinated peptides revealed key residues of several complementarity-determining regions that recognized the citrulline as well as the neighboring peptide backbone, but with limited contact with the side chains of the peptides. The same citrullinated peptides were recognized by high titers of serum autoantibodies in 2 large cohorts of RA patients. CONCLUSION: These data show, for the first time, how ACPAs derived from human RA serum recognize citrulline. The specific citrulline recognition and backbone-mediated interactions provide a structural explanation for the promiscuous recognition of citrullinated peptides by RA-specific ACPAs. Structural Basis of Cross-Reactivity of Anti-Citrullinated Protein Antibodies.,Ge C, Xu B, Liang B, Lonnblom E, Lundstrom SL, Zubarev RA, Ayoglu B, Nilsson P, Skogh T, Kastbom A, Malmstrom V, Klareskog L, Toes REM, Rispens T, Dobritzsch D, Holmdahl R Arthritis Rheumatol. 2019 Feb;71(2):210-221. doi: 10.1002/art.40698. Epub 2019, Jan 4. PMID:30152126 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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