Disease relevance of CDR1

• The role of polymorphisms and differential expression of individual V genes in multigenic autoimmune diseases, as well as the organization and expression of individual V genes, can be examined with pairs of oligonucleotides from CDR1 and the 3' end of CDR2, or with probes from the 5' end of CDR2 [1].
• Expression of monovalent fragments derived from a human IgM autoantibody in E. coli. The input of the somatically mutated CDR1/CDR2 and of the CDR3 into antigen binding specificity [2].
• A single arginine-to-serine mutation in light-chain CDR1 of B3 reduced binding to both those antigens and may also have reduced the pathogenicity of the expressed antibodies in severe combined immunodeficiency (SCID) mice [3].
• We found that a synthetic peptide corresponding to CDR1 sequence contains a functional T-cell epitope able to evoke a major histocompatibility complex (MHC) class II-dependent T-cell proliferative response and cytokine release without direct cytotoxicity for peptide-pulsed target or fresh autologous lymphoma cells [4].
• Hypermutations were found in low-grade lymphomas throughout CDR1-CDR3 suggestive of positive selection through their antigen receptor [5].

Psychiatry related information on CDR1

• According to their Clinical Dementia Rating scores, subjects were classified into mild (CDR1; n=11) and moderate (CDR2; n=9) dementia patients [6].
• The sequences of several 8.12+ and 8.12- V lambda II genes are reported here and are used to map the 8.12 Id to the vicinity of CDR1, as well as to further characterize the large and polymorphic V lambda II gene family [7].
• Autoantibody anti-CDR1 spectrotype analyses detected individual differences among patients, but 5 of 8 patients characterized in detail showed elevated IgG binding to CDR1 peptide epitopes of V beta 6.1, 21.1 and 22.1 gene products [8].
• Three hundred and forty participants were of Clinical Dementia Rating (CDR) 0 (healthy), 113 were of CDR 0.5 (questionable dementia), and 32 were of CDR 1 and 2 (including 20 Alzheimer's disease, AD) [9].

High impact information on CDR1

• These preliminary results suggest that CDR1 and CDR2 may be less variable in structure than their immunoglobulin counterparts, consistent with the idea that they may interact preferentially with the less polymorphic regions of the molecules of the major histocompatibility complex [10].
• We propose a general model for Ni(2+) recognition in which betaHis81 and two amino acids from the NH(2)-terminal part of the MHC bound peptide coordinate Ni(2+) which then interacts with some portion of the Valpha CDR1 or CDR2 region [11].
• Thus, the MYPPPY motifs of CTLA4Ig and CD28Ig are important for their binding to B7-1, but the increased strength of this binding by CTLA4Ig is mediated by nonconserved residues in the CDR1- and CDR3-analogous regions [12].
• Three new public idiotopes, which were common to monoclonal antibodies from all three patients, were defined by five polyclonal rabbit antiidiotypes, two monoclonal mouse antiidiotopes, and a monoclonal mouse antibody against a synthetic peptide that contains residues of the heavy chain CDR-1 of a monoclonal lupus anti-DNA antibody [13].
• The hCDR1-induced CD4+CD25+ cells suppressed autoreactive CD4+ cells, resulting in reduced rates of activation-induced apoptosis [14].

Chemical compound and disease context of CDR1

• Here we show that disruption of C. glabrata PDR1 conferred equivalent fluconazole hypersensitivity (MIC = 2 microg ml(-1)) to both F15 and 66032 and eliminated both constitutive and fluconazole-induced CDR1-PDH1 expression [15].
• Inhibition of CDR-1 expression renders C. elegans susceptible to cadmium toxicity [16].
• We conclude that specific treatment with hCDR1 ameliorates murine lupus via distinct mechanisms of action than those of dexamethasone [17].
• Treatment with hCDR1 resulted in a significant amelioration of the clinical features manifested by proteinuria, human IgG complex deposits as well as deposits of murine complement C3 [18].

Biological context of CDR1

• We found that point mutations in multiple residues of CDR1 produced effects on IgA binding ranging from minimal (90% of control) to profound (7%) [19].
• M4, a mutation with three amino acid substitutions in CDR1, was isolated by screening the library with an enzyme conjugate of synthetic Le(y) tetrasaccharide (sLe(y)) [20].
• H chain CDR3, flanked by H chain CDR1 and L chain CDRs 2 and 3, builds specificity at the center of the antigen binding site [21].
• We then characterized these mAbs for their reactivity toward three mutants of the human CD8 alpha carrying amino acid sequence changes in the surface-exposed loops homologous to the immunoglobulin CDR1, 2, and 3 [22].
• Moreover, the CDR1 region, although in sequence homologous to human CDR1, deviates fundamentally from the canonical structure [23].

Anatomical context of CDR1

• For example, the in-to-out activity associated with Cdr1p and Cdr2p is energy-dependent and sensitive to sulphydryl blocking agents such as N-ethylmaleimide (NEM) and cytoskeleton disrupting agent cytochalasin E, while Cdr3p-associated out-to-in activity is energy-dependent but insensitive to NEM and cytochalasin E [24].
• Using this system, we have explored the sequence requirements for CDR1 and CDR2 of the TCR alpha-chain in a human T cell response characterized by restricted Valpha and Vbeta usage [25].
• Following screening of culture supernatants from over 60 Epstein-Barr virus-carrying B-cell lines of normal and neoplastic origin, we identified a line, IARC307, that secretes an IgM kappa protein showing marked specificity for the V beta 8.1 CDR1 sequence CKPISGHNSLFQWYRQT [26].
• In addition, increased Cdr1p levels were immunodetected in the cell membrane fractions of all the TIMM strains except for TIMM 3164 [27].
• Intriguingly, all 10 Vkappa1C hybridomas share a lysine to glutamate mutation in the CDR1 [28].

Associations of CDR1 with chemical compounds

• B-CLL V(H) mutations concentrated in complementarity-determining region 1 (CDR1) and CDR2, which exhibited higher replacement-to-silent ratios (CDR R/S, 4.60; framework region [FR] R/S, 1.72) [29].
• These results suggest that energy-dependent drug efflux associated with increased expression of CDR1 and CDR2 is involved in the fluconazole resistance mechanisms in two of the four isolates, TIMM 3165 and TIMM 3166 [27].
• The TCR CDR3s of both alpha and beta chains are particularly rich in Gly, whereas the CDR1 and CDR2 loops exhibit strong biases in favour of charged residues [30].
• However, the frequent occurrence of additional Cys residues in both the CDR1 and CDR3 might lead to the formation of a second internal disulfide bridge, thereby stabilizing the CDR structure as in the DAW antibody [31].
• In CDR exchange studies, VL containing B3VL CDR1 were associated with elevated CL binding, which was reduced significantly by substitution of a CDR1 arginine residue at position 27a with serine [32].

Physical interactions of CDR1

• The conservative F substitution of Y 26 in the CDR1-like region also reduced binding to CD80 and CD86 [33].
• Expression of the FAI (formation of syncytia by shifting from 16 to 37 degrees C) remains sensitive to sCD4, shedding of gp120, and MAb directed toward CDR-1/2 but is less sensitive to MAb that bind CDR-3 and is insensitive to PI [34].
• The protein REI-RGD34--produced by inserting the sequence RIPRGDMP into the CDR1 loop region of the immunoglobulin VL domain REI--strongly inhibits fibrinogen binding to the integrins alpha IIb beta 3 and alpha V beta 3 [35].

Other interactions of CDR1

• The CDR1 and CDR2 loops contributed minimal energy through direct recognition of the antigen and instead had a chief function in stabilizing the ligated CDR3 loops [36].
• The structure of pIgR domain 1 reveals a folding topology similar to immunoglobulin variable domains, but with differences in the counterparts of the complementarity determining regions (CDRs), including a helical turn in CDR1 and a CDR3 loop that points away from the other CDRs [37].
• Evaluation of candidate genes CDR1 and SOX3 did not reveal mutations in affected male subjects [38].
• The ability to substitute CDR-like loops within CTLA-4 will enable design and construction of more complex libraries of single V-like domain binding molecules [39].
• These included genes involved in small molecule transport (HGT11, HXT5, ENA22, PHO84, CDR4), iron uptake (FRE30, FET34, FTR1, FTR2, SIT1) and cell stress (SOD1, SOD22, CDR1, DDR48) [40].

Analytical, diagnostic and therapeutic context of CDR1

• The extreme lability of this context was also shown by the fact that transplantation of the CDR1, -2, and -3 loops from the beta chain of 5C.C7 onto a V beta 1 framework failed to transfer MHC-peptide specificity even when the TCR-alpha chains were identical [41].
• One candidate VL domain-specific for B7.1 was affinity matured by simultaneous randomisation of all CDR loops using DNA shuffling with degenerate CDR-spiking oligonucleotides [42].
• Using x-ray crystallography, we have characterized the three-dimensional structure of the anti-id mAb MK2-23 Fab' and shown that its heavy chain complementarity-determining region (CDR3) (H3) and its light chain CDR1 (L1) are closely associated [43].
• By PCR, C. dubliniensis was also found to encode homologs of CDR1 and CDR2, termed CdCDR1 and CdCDR2, respectively [44].
• In this study, we determined the nature of any immune responses generated by peptides corresponding to the complementarity-determining region 1 (CDR1) and complementarity-determining region 2 (CDR2) sequences of idiotypic heavy chain variable region (VH) to identify the clinical potential of the peptides for immunotherapy of lymphoma [4].

References