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S1 Domain (s1 + domain)

Distribution by Scientific Domains

Chemistry	50%

Selected Abstracts

Severe acute respiratory syndrome coronavirus entry into host cells: Opportunities for therapeutic intervention,

MEDICINAL RESEARCH REVIEWS, Issue 4 2006
Kap-Sun Yeung
Abstract A novel human coronavirus (CoV) has been identified as the etiological agent that caused the severe acute respiratory syndrome (SARS) outbreak in 2003. The spike (S) protein of this virus is a type I surface glycoprotein that mediates binding of the virus to the host receptor and the subsequent fusion between the viral and host membranes. Because of its critical role in viral entry, the S protein is an important target for the development of anti-SARS CoV therapeutics and prophylactics. This article reviews the structure and function of the SARS CoV S protein in the context of its role in virus entry. Topics that are discussed include: the interaction between the S1 domain of the SARS spike protein and the cellular receptor, angiotensin converting enzyme 2 (ACE2), and the structural features of the ectodomain of ACE2; the antigenic determinants presented by the S protein and the nature of neutralizing monoclonal antibodies that are elicited in vivo; the structure of the 4,3-hydrophobic heptad repeats HR1 and HR2 of the S2 domain and their interaction to form a six-helical bundle during the final stages of fusion. Opportunities for the design and development of anti-SARS agents based on the inhibition of receptor binding, the therapeutic uses of S-directed monoclonal antibodies and inhibitors of HR1,HR2 complex formation are presented. © 2006 Wiley Periodicals, Inc. Med Res Rev, 26, No. 4, 414,433, 2006 [source]

Characterization of a comparative model of the extracellular domain of the epidermal growth factor receptor

PROTEIN SCIENCE, Issue 2 2000
Robert N. Jorissen
Abstract The Epidermal Growth Factor (EGF) receptor is a tyrosine kinase that mediates the biological effects of ligands such as EGF and transforming growth factor alpha. An understanding of the molecular basis of its action has been hindered by a lack of structural and mutational data on the receptor. We have constructed comparative models of the four extracellular domains of the EGF receptor that are based on the structure of the first three domains of the insulin-like growth factor-1 (IGF-1) receptor. The first and third domains of the EGF receptor, L1 and L2, are right-handed beta helices. The second and fourth domains of the EGF receptor, S1 and S2, consist of the modules held together by disulfide bonds, which, except for the first module of the S1 domain, form rod-like structures. The arrangement of the L1 and S1 domains of the model are similar to that of the first two domains of the IGF-1 receptor, whereas that of the L2 and S2 domains appear to be significantly different. Using the EGF receptor model and limited information from the literature, we have proposed a number of regions that may be involved in the functioning of the receptor. In particular, the faces containing the large beta sheets in the L1 and L2 domains have been suggested to be involved with ligand binding of EGF to its receptor. [source]

Mechanisms by which atrial fibrillation-associated mutations in the S1 domain of KCNQ1 slow deactivation of IKs channels

THE JOURNAL OF PHYSIOLOGY, Issue 17 2008
Lioara Restier
The slow delayed rectifier K+ current (IKs) is a major determinant of action potential repolarization in the heart. IKs channels are formed by coassembly of pore-forming KCNQ1 ,-subunits and ancillary KCNE1 ,-subunits. Two gain of function mutations in KCNQ1 subunits (S140G and V141M) have been associated with atrial fibrillation (AF). Previous heterologous expression studies found that both mutations caused IKs to be instantaneously activated, presumably by preventing channel closure. The purpose of this study was to refine our understanding of the channel gating defects caused by these two mutations located in the S1 domain of KCNQ1. Site-directed mutagenesis was used to replace S140 or V141 with several other natural amino acids. Wild-type and mutant channels were heterologously expressed in Xenopus oocytes and channel function was assessed with the two-microelectrode voltage clamp technique. Long intervals between voltage clamp pulses revealed that S140G and V141M KCNQ1-KCNE1 channels are not constitutively active as previously reported, but instead exhibit extremely slow deactivation. The slow component of IKs deactivation was decreased 62-fold by S140G and 140-fold by the V141M mutation. In addition, the half-point for activation of these mutant IKs channels was ,50 mV more negative than wild-type channels. Other substitutions of S140 or V141 in KCNQ1 caused variable shifts in the voltage dependence of activation, but slowed IKs deactivation to a much lesser extent than the AF-associated mutations. Based on a published structural model of KCNQ1, S140 and V141 are located near E160 in S2 and R237 in S4, two charged residues that could form a salt bridge when the channel is in the open state. In support of this model, mutational exchange of E160 and R237 residues produced a constitutively open channel. Together our findings suggest that altered charge-pair interactions within the voltage sensor module of KCNQ1 subunits may account for slowed IKs deactivation induced by S140 or V141. [source]

Determinants of activation kinetics in mammalian hyperpolarization-activated cation channels

THE JOURNAL OF PHYSIOLOGY, Issue 1 2001
Takahiro M. Ishii
1The structural basis for the different activation kinetics of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels was investigated with the whole-cell patch clamp technique by using HCN1, HCN4, chimeric channels and mutants in a mammalian expression system (COS,7). 2The activation time constant of HCN4 was about 40-fold longer than that of HCN1 when compared at ,100 mV. 3In chimeras between HCN1 and HCN4, the region of the S1 transmembrane domain and the exoplasmic S1-S2 linker markedly affected the activation kinetics. The cytoplasmic region between S6 and the cyclic nucleotide-binding domain (CNBD) also significantly affected the activation kinetics. 4The S1 domain and S1-S2 linker of HCN1 differ from those of HCN4 at eight amino acid residues, and each single point mutation of them changed the activation kinetics less than 2-fold. However, the effects of those mutations were additive and the substitution of the whole S1 and S1-S2 region of HCN1 by that of HCN4 resulted in a 10, to 20-fold slowing. 5The results indicate that S1 and S1-S2, and S6-CNBD are the crucial components for the activation gating of HCN channels. [source]