RASMOL: biomolecular graphics for all

Sayle, Roger A.

doi:10.1016/s0968-0004(00)89080-5

Cited by 2,475 publications

(1,468 citation statements)

References 6 publications

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“…3 Localisation of residues D160, K161, M235, R308 and R397 on the structural model for beta cell GCK. The closed conformation (1V4S) of wild-type GCK [30] is represented using the RasMol program [36]. Selected residues are indicated as clusters of coloured balls.…”

Section: Discussionmentioning

confidence: 99%

Functional analysis of human glucokinase gene mutations causing MODY2: exploring the regulatory mechanisms of glucokinase activity

et al. 2006

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Aims/hypothesis Glucokinase (GCK) acts as a glucose sensor in the pancreatic beta cell and regulates insulin secretion. In the gene encoding GCK the heterozygous mutations that result in enzyme inactivation cause MODY2. Functional studies of naturally occurring GCK mutations associated with hyperglycaemia provide further insight into the biochemical basis of glucose sensor regulation. Materials and methods Identification of GCK mutations in selected MODY patients was performed by single-strand conformation polymorphism and direct sequencing. The kinetic parameters and thermal stability of recombinant mutant human GCK were determined, and in pull-down assays the effect of these mutations on the association of GCK with glucokinase (hexokinase 4) regulator (GCKR, also known as glucokinase regulatory protein [GKRP]) and 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKFB1, also known as PFK2) was tested. Results We identified three novel GCK mutations: the insertion of an asparagine residue at position 161 (inserN161) and two missense mutations (M235V and R308W). We also identified a fourth mutation (R397L) reported in a previous work. Functional characterisation of these mutations revealed that insertion of asparagine residue N161 fully inactivates GCK, whereas the M235V and R308W mutations only partially impair enzymatic activity. In contrast, GCK kinetics was almost unaffected by the R397L mutation. Although none of these mutations affected the interaction of GCK with PFKFB1, we found that the R308W mutation caused protein instability and increased the strength of interaction with GCKR. Conclusions/interpretation Our results show that different MODY2 mutations impair GCK function through different mechanisms such as enzymatic activity, protein stability and increased interaction with GCKR, helping further elucidate the regulation of GCK activity.

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Section: Discussionmentioning

confidence: 99%

Functional analysis of human glucokinase gene mutations causing MODY2: exploring the regulatory mechanisms of glucokinase activity

et al. 2006

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“…The mutation of 252 Arg to Cys could favour the formation of an abnormal disulfide bond between 3 Cys and 252 Cys, that might lock the L1 module and Cys-rich module together into a conformation unfavourable for high affinity binding. Other mismatches with other cysteines from the Cys-rich region could also occur, especially with 253 Cys, resulting in a disturbed 3-D structure [36,37,38].…”

Section: Discussionmentioning

confidence: 99%

An arginine to cysteine252 mutation in insulin receptors from a patient with severe insulin resistance inhibits receptor internalisation but preserves signalling events

et al. 2002

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Aims/hypothesis. We examined the properties of a mutant insulin receptor (IR) with an Arg 252 to Cys (IR R252C ) substitution in the α-subunit originally identified in a patient with extreme insulin resistance and acanthosis nigricans. Methods. We studied IR cell biology and signalling pathways in Chinese Hamster Ovary cells overexpressing this IR R252C . Results. Our investigation showed an impairment in insulin binding to IR R252C related mostly to a reduced affinity of the receptor for insulin and to a reduced rate of IR R252C maturation; an inhibition of IR R252C -mediated endocytosis resulting in a decreased insulin degradation and insulin-induced receptor down-regulation; a maintenance of IR R252C on microvilli even in the presence of insulin; a similar autophosphorylation of mutant IR R252C followed by IRS 1/IRS 2 phosphorylation, p85 association with IRS 1 and IRS 2 and Akt phosphorylation similar to those observed in cells expressing wild type IR (IRwt); and finally, a reduced insulin-induced Shc phosphorylation accompanied by decreased ERK1/2 phosphorylation and activity and of thymidine incorporation into DNA in cells expressing IR R252C as compared to cells expressing IRwt. Conclusion/interpretation. These observations suggest that: parameters other than tyrosine kinase activation participate in or control the first steps of IR internalisation or both; IR-mediated IRS 1/2 phosphorylation can be achieved from the cell surface and microvilli in particular; Shc phosphorylation and its subsequent signalling pathway might require IR internalisation; defective IR endocytosis correlates with an enhancement of some biological responses to insulin and attenuation of others. [Diabetologia (2002) 45:657-667]

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“…In some cases, MUSASHI (http://musashi.sourceforge.jp/), DSSP [10], and Rasmol [11] programs were used. The database functionality was implemented using the Oracle 10 g software, operating on AIX 5.3 L Unix and IBM p570 server system (POWER5 ?…”

Section: Methodsmentioning

confidence: 99%

ProSeg: a database of local structures of protein segments

Sawada

Honda

2008

J Comput Aided Mol Des

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Integration of knowledge on the sequencestructure correlation of proteins provides a basis for the structural design of artificial novel proteins. As one of strategies, it is effective to consider a short segment, whose size is in between an amino acid and a domain, as a correlation unit for exploring the structure-to-sequence relationship. Here we report the development of a database called ProSeg, which consists of two sub-databases, Segment DB and Cluster DB. Segment DB contains tens of thousands of segments that were prepared by dividing the primary sequences of 370 proteins using a sliding L-residue window (L = 5, 9, 11, 15). These segments were classified into several thousands of clusters according to their threedimensional structural resemblance. Cluster DB contains much cluster-related information, which includes image, rank, frequency, secondary structure assignment, sequence profile, etc. Users can search for a suitable cluster by inputting an appropriate parameter (i.e., PDB ID, dihedral angles, or DSSP symbols), which identifies the backbone structure of a query segment. Analogous to a language, ProSeg could be regarded as a 'structure-sequence dictionary' that contains over 10,000 'protein words'. ProSeg is freely accessible through the Internet (http://riodb.ibase. aist.go.jp/proseg/).

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RASMOL: biomolecular graphics for all

Cited by 2,475 publications

References 6 publications

Functional analysis of human glucokinase gene mutations causing MODY2: exploring the regulatory mechanisms of glucokinase activity

Functional analysis of human glucokinase gene mutations causing MODY2: exploring the regulatory mechanisms of glucokinase activity

An arginine to cysteine252 mutation in insulin receptors from a patient with severe insulin resistance inhibits receptor internalisation but preserves signalling events

ProSeg: a database of local structures of protein segments

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