共查询到20条相似文献,搜索用时 31 毫秒
1.
《Trends in biochemical sciences》2002,27(9):438-440
The PASTA domain (for penicillin-binding protein and serine/threonine kinase associated domain) is found in the high molecular weight penicillin-binding proteins and eukaryotic-like serine/threonine kinases of a range of pathogens. We describe this previously uncharacterized domain and infer that it binds β-lactam antibiotics and their peptidoglycan analogues. We postulate that PknB-like kinases are key regulators of cell-wall biosynthesis. The essential function of these enzymes suggests an additional pathway for the action of β-lactam antibiotics. 相似文献
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Background
Protein interactions are thought to be largely mediated by interactions between structural domains. Databases such as iPfam relate interactions in protein structures to known domain families. Here, we investigate how the domain interactions from the iPfam database are distributed in protein interactions taken from the HPRD, MPact, BioGRID, DIP and IntAct databases. 相似文献4.
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T-protein is composed of chorismate mutase (AroQ(T)) fused to the N-terminus of prephenate dehydrogenase (TyrA). Here, we report the replacement of AroQ(T) with the β1-domain of protein G (Gβ1). The TyrA domain shows a strong dehydrogenase activity within the context of this fusion, and our data indicate that Gβ1-TyrA folds into a dimeric conformation. Amino acid substitutions in the Gβ1 domain of Gβ1-TyrA identified residues involved in stabilizing the TyrA dimeric conformation. Gβ1 substitutions in the N-terminal β-hairpin eliminated Gβ1-TyrA expression, whereas Gβ1-TyrA tolerated Gβ1 substitutions in the C-terminal β-hairpin and in the α-helix. All of the characterized variants folded into a dimeric conformation. The importance of the β2-strand in forming a Gβ1 homo-dimerization interface explains the relevance of the first-β-hairpin in stabilizing the dimeric TyrA protein. 相似文献
6.
NMR structural determination of large multi-domain proteins is a challenging task due to significant spectral overlap with
a particular difficulty in unambiguous identification of domain–domain interactions. Segmental labeling is a NMR strategy
that allows for isotopically labeling one domain and leaves the other domain unlabeled. This significantly simplifies spectral
overlaps and allows for quick identification of domain–domain interaction. Here, a novel segmental labeling strategy is presented
for detection of inter-domain NOEs. To identify domain–domain interactions in human apolipoprotein E (apoE), a multi-domain,
299-residues α-helical protein, on-column expressed protein ligation was utilized to generate a segmental-labeled apoE samples
in which the N-terminal (NT-) domain was 2H(99%)/15N-labeled whereas the C-terminal (CT-) domain was either 15N- or 15N/13C-labeled. 3-D 15N-edited NOESY spectra of these segmental-labeled apoE samples allow for direct observation of the inter-domain NOEs between
the backbone amide protons of the NT-domain and the aliphatic protons of the CT-domain. This straightforward approach permits
unambiguous identification of 78 inter-domain NOEs, enabling accurate definition of the relative positions of both the NT-
and the CT-domains and determination of the NMR structure of apoE. 相似文献
7.
Numerous studies have used the atomic level structure of the isolated ligand binding domain of the glutamate receptor to elucidate the agonist-induced activation and desensitization processes in this group of proteins. However, no study has demonstrated the structural equivalence of the isolated ligand binding fragments and the protein in the native receptor. In this report, using visible absorption spectroscopy we show that the electronic environment of the antagonist 6-cyano-7-nitro-2,3-dihydroxyquinoxaline is identical for the isolated protein and the native glutamate receptors expressed in cells. Our results hence establish that the local structure of the ligand binding site is the same in the two proteins and validate the detailed structure-function relationships that have been developed based on a comparison of the structure of the isolated ligand binding domain and electrophysiological consequences in the native receptor. 相似文献
8.
The eukaryotic genome is organized into functionally and structurally distinct domains, representing regulatory units for gene expression and chromosome behavior. DNA sequences that mark the border between adjacent domains are the insulators or boundary elements, which are required in maintenance of the function of different domains. Some insulators need others enable to play insulation activity. Chromatin domains are defined by distinct sets of post-translationally modified histones. Recent studies show that these histone modifications are also involved in establishment of sharp chromatin boundaries in order to prevent the spreading of distinct domains. Additionally, in some loci, the high-order chromatin structures for long-range looping interactions also have boundary activities, suggesting a correlation between insulators and chromatin loop domains. In this review, we will discuss recent progress in the field of chromatin domain boundaries. 相似文献
9.
Van der Meer SF Jaspers RT Degens H 《Journal of musculoskeletal & neuronal interactions》2011,11(4):286-297
It has been suggested that the number of myonuclei in a muscle fibre changes in proportion to the change in fibre size, resulting in a constant myonuclear domain size, defined as the cytoplasmic volume per myonucleus. The myonuclear domain size varies, however, between fibre types and is inversely related with the oxidative capacity of a fibre. Overall, the observations of an increase in myonuclear domain size during both maturational growth and overload-induced hypertrophy, and the decrease in myonuclear domain size during disuse- and ageing-associated muscle atrophy suggest that the concept of a constant myonuclear domain size needs to be treated cautiously. It also suggests that only when the myonuclear domain size exceeds a certain threshold during growth or overload-induced hypertrophy acquisition of new myonuclei is required for further fibre hypertrophy. 相似文献
10.
《MABS-AUSTIN》2013,5(6):625-638
We report preclinical data for CEP-37247, the first human framework domain antibody construct to enter the clinic. At approximately 11 – 13kDa, domain antibodies or dAbs are the smallest antibody domain able to demonstrate the antigen-recognition function of an antibody, e.g. high selectivity and affinity for target antigen. CEP-37247 is a bivalent anti-tumor necrosis factor (TNF)α domain antibody protein construct combining the antigen-recognition function of a dAb with the pharmacological advantages of an antibody Fc region. As a homodimer, with each chain comprising VL dAb, truncated CH1, hinge, CH2 and CH3 domains, CEP-37247 has a molecular mass of approximately 78kDa, which is about half the size of a conventional IgG molecule. Surface plasmon resonance data demonstrate that CEP-37247 possesses high selectivity and affinity for TNFα. CEP-37247 is a potent neutralizer of TNFα activity in vitro in the L929 TNF-mediated cytotoxicity assay. In a human TNFα-over-expressing mouse model of polyarthritis, CEP-37247 prevents development of disease, and is at least as effective as the marketed product etanercept. Fc functionality is intact – CEP-37247 is capable of mediating antibody-dependent cell-mediated cytotoxicity and has a circulating half-life of approximately 4.5 days in cynomolgus macaques. Given the favorable properties outlined above, and its high expression levels (approaching 7 g/L) in a CHOK1 based-expression system, CEP-37247 is progressing into the clinic, where other potential advantages such as enhanced efficacy due to improved tissue distribution, and beneficial immunogenicity profile, will be evaluated. 相似文献
11.
Ramachandra M. Bhaskara Alexandre G. de Brevern 《Journal of biomolecular structure & dynamics》2013,31(12):1467-1480
Inter-domain linkers (IDLs)’ bridge flanking domains and support inter-domain communication in multi-domain proteins. Their sequence and conformational preferences enable them to carry out varied functions. They also provide sufficient flexibility to facilitate domain motions and, in conjunction with the interacting interfaces, they also regulate the inter-domain geometry (IDG). In spite of the basic intuitive understanding of the inter-domain orientations with respect to linker conformations and interfaces, we still do not entirely understand the precise relationship among the three. We show that IDG is evolutionarily well conserved and is constrained by the domain–domain interface interactions. The IDLs modulate the interactions by varying their lengths, conformations and local structure, thereby affecting the overall IDG. Results of our analysis provide guidelines in modelling of multi-domain proteins from the tertiary structures of constituent domain components. 相似文献
12.
DNA polymerase β (Pol β) is a 39-kDa enzyme that performs the vital cellular function of repairing damaged DNA. Mutations in Pol β have been linked to various cancers, and these mutations are further correlated with altered Pol β enzymatic activity. The fidelity of correct nucleotide incorporation into damaged DNA is essential for Pol β repair function, and several studies have implicated conformational changes in Pol β as a determinant of this repair fidelity. In this work, the rate constants for domain motions in Pol β have been determined by solution NMR relaxation dispersion for the apo and substrate-bound, binary forms of Pol β. In apo Pol β, molecular motions, primarily isolated to the DNA lyase domain, are observed to occur at 1400 s(-1). Additional analysis suggests that these motions allow apo Pol β to sample a conformation similar to the gapped DNA-substrate-bound form. Upon binding DNA, these lyase domain motions are significantly quenched, whereas evidence for conformational motions in the polymerase domain becomes apparent. These NMR studies suggest an alteration in the dynamic landscape of Pol β due to substrate binding. Moreover, a number of the flexible residues identified in this work are also the location of residues, which upon mutation lead to cancer phenotypes in vivo, which may be due to the intimate role of protein motions in Pol β fidelity. 相似文献
13.
Collagens are the most abundant proteins in the mammalian body and it is well recognized that collagens fulfill an important structural role in the extracellular matrix in a number of tissues. Inactivation of the collagen alpha 1(I) gene in mice results in embryonic lethality and collagen mutations in humans cause defects leading to disease. Integrins constitute a major group of receptors for extracellular matrix components, including collagens. Currently four collagen-binding I domain-containing integrins are known, namely alpha 1 beta 1, alpha 2 beta 1, alpha 10 beta 1 and alpha 11 beta 1. Unlike the undisputed role of collagens as structural elements, the biological importance of integrin mediated cell-collagen interactions is far from clear. This is in part due to the limited information available on the most recent additions of the integrin family, alpha 10 beta 1 and alpha 11 beta 1. Future studies using gene inactivation of individual and multiple integrin genes will allow testing of the hypothesis that collagen-binding integrins have redundant functions but will also shed light on their importance in pathological conditions. In this review we will describe what is currently known about the collagen-binding integrins and discuss their biological functions. 相似文献
14.
Integrin conformational changes mediate integrin activation and signaling triggered by intracellular molecules or extracellular ligands. Even though it is known that αβ transmembrane domain separation is required for integrin signaling, it is still not clear how this signal is transmitted from the transmembrane domain through two long extracellular legs to the ligand-binding headpiece. This study addresses whether the separation of the membrane-proximal extracellular αβ legs is critical for integrin activation and outside-in signaling. Using a disulfide bond to restrict dissociation of the α-subunit Calf-2 domain and β-subunit I-EGF4 domain, we were able to abolish integrin inside-out activation and outside-in signaling. In contrast, disrupting the interface by introducing a glycosylation site into either subunit activated integrins for ligand binding through a global conformational change. Our results suggest that the interface of the Calf-2 domain and the I-EGF4 domain is critical for integrin bidirectional signaling. 相似文献
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Two distinct variants of erythrocyte spectrin βIV domain 总被引:15,自引:7,他引:8
B. Pothier N. Alloisio L. Morle J. Maréchal H. Barthélemy M. T. Ducluzeau A. Dorier J. Delaunay 《Human genetics》1989,81(4):373-376
Summary Thirty-nine Turkish phenylketonuria (PKU) families were investigated for their DNA haplotypes at the phenylalanine hydroxylase
(PAH) locus. There was a threefold higher incidence of consanguinity in the population studied compared with the general Turkish
population. The PAH DNA haplotype 6 was found to be almost exclusively associated not only with the mutant PAH genes but also
with the classic phenotype in 39% of the Turkish patients. This haplotype was of no importance in northern European populations.
The two DNA haplotypes (1 and 4) that were almost equally frequent among the normal and the mutant PAH genes in northern European
populations show virtually the same distribution in Turkish individuals. In all populations studied, these haplotypes are
associated with different phenotypes. 相似文献
17.
Muhammad H. Zaman Mohammad R. Kaazempur-Mofrad 《Molecular & cellular biomechanics : MCB》2004,1(4):291-302
α-actinin, an actin binding protein, plays a key role in cell migration, cross-links actin filaments in the Z-disk, and is a major component of contractile muscle apparatus. The flexibility of the molecule is critical to its function. The flexibility of various regions of the molecule, including the linker connecting central subunits is studied using constant force steered molecular dynamics simulations. The linker, whose structure has been a subject of debate, is predicted to be semi-flexible. The flexibility of the linker is compared to all possible segments of equal length throughout the molecule. The stretching profile of the molecule at different forces suggests that loops and regions adjacent to the loops are much more rigid than the helices in the protein. Amino acid composition analysis of most flexible and most rigid regions of the molecule reveals that the rigid regions are rich in Ser, Val and Ile whereas the flexible regions are rich in Ala, Leu and Glu. 相似文献
18.
Shakespeare WC 《Current opinion in chemical biology》2001,5(4):409-415
The past two years have witnessed a number of significant advances in the design of SH2 inhibitors of both Src and Grb2. For Src, several non-peptide templates have been developed with high affinity, and one case, in the context of bone-binding phosphotyrosine bioisostere, has yielded an in vivo active antiresorptive agent. Similarly, high-affinity Grb2 SH2 inhibitors with novel phosphotyrosine replacements have now been reported that demonstrate, for the first time, cellular activities consistent with an anticancer agent. 相似文献
19.
To date, very few βγ-crystallins have been identified and structurally characterized. Several of them have been shown to bind Ca(2+) and thereby enhance their stability without any significant change in structure. Although Ca(2+)-induced conformational changes have been reported in two putative βγ-crystallins from Caulobacter crescentus and Yersinia pestis, they are shown to be partially unstructured, and whether they acquire a βγ-crystallin fold is not known. We describe here a βγ-crystallin domain, hahellin, its Ca(2+) binding properties and NMR structure. Unlike any other βγ-crystallin, hahellin is characterized as a pre-molten globule (PMG) type of natively unfolded protein domain. It undergoes drastic conformational change and acquires a typical βγ-crystallin fold upon Ca(2+) binding and hence acts as a Ca(2+)-regulated conformational switch. However, it does not bind Mg(2+). The intrinsically disordered Ca(2+)-free state and the close structural similarity of Ca(2+)-bound hahellin to a microbial βγ-crystallin homologue, Protein S, which shows Ca(2+)-dependent stress response, make it a potential candidate for the cellular functions. This study indicates the presence of a new class of natively unfolded βγ-crystallins and therefore the commencement of the possible functional roles of such proteins in this superfamily. 相似文献
20.
Jeffrey L. Mills Thomas B. Acton Rong Xiao John K. Everett Gaetano T. Montelione Thomas Szyperski 《Journal of structural and functional genomics》2013,14(1):19-24
A high-quality NMR structure of the helicase associated (HA) domain comprising residues 627–691 of the 753-residue protein BVU_0683 from Bacteroides vulgatus exhibits an all α-helical fold. The structure presented here is the first representative for the large protein domain family PF03457 (currently 742 members) of HA domains. Comparison with structurally similar proteins supports the hypothesis that HA domains bind to DNA and that binding specificity varies greatly within the family of HA domains constituting PF03457. 相似文献