Evaluation of comparative protein modeling by M<scp>ODELLER</scp>

Šali, Andrej; Potterton, Liz; Feng, Yanghe; Vlijmen, Herman van; Karplus, Martin

doi:10.1002/prot.340230306

Cited by 1,045 publications

(723 citation statements)

References 36 publications

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“…The use of constraint-based potentials for evaluating backbone structures may be the most conservative approach for the incorporation of backbonē exibility into core optimization or comparative modeling algorithms (Sali et al, 1995). In our PLG potential, we placed particular emphasis on the preservation of local geometry since it is strongly conserved in sets of variants whose structures have been analyzed.…”

Section: Discussionmentioning

confidence: 99%

Side-chain and backbone flexibility in protein core design 1 1Edited by A. R. Fersht

Desjarlais

Handel

1999

Journal of Molecular Biology

135

105

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We have developed a computational approach for the design and prediction of hydrophobic cores that includes explicit backbone¯exibility. The program consists of a two-stage combination of a genetic algorithm and monte carlo sampling using a torsional model of the protein. Backbone structures are evaluated either by a canonical force-®eld or a constraining potential that emphasizes the preservation of local geometry. The utility of the method for protein design and engineering is explored by designing three novel hydrophobic core variants of the protein 434 cro. We use the new method to evaluate these and previously designed 434 cro variants, as well as a series of phage T4 lysozyme variants. In order to properly evaluate the in¯uence of backbone¯exibility, we have also analyzed the effects of varying amounts of side-chain¯exibility on the performance of ®xed backbone methods. Comparison of results using a ®xed versus¯exible backbone reveals that, surprisingly, the two methods are almost equivalent in their abilities to predict relative experimental stabilities, but only when full side-chain¯exibility is allowed. The prediction of core side-chain structure can vary dramatically between methods. In some, but not all, cases the¯exible backbone method is a better predictor of structure. The development of a¯exible backbone approach to core design is particularly important for attempts at de novo protein design, where there is no prior knowledge of a precise backbone structure.

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Section: Discussionmentioning

confidence: 99%

Side-chain and backbone flexibility in protein core design 1 1Edited by A. R. Fersht

Desjarlais

Handel

1999

Journal of Molecular Biology

135

105

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“…The template was selected using HHPRED (22). The model was built using Modeller (23). The model structure was refined using the Rosetta Relax protocol (v. 3.2) (24).…”

Section: Structural Model Construction Of Kl1 and Kl2 Domainsmentioning

confidence: 99%

Tumor Suppressor Activity of Klotho in Breast Cancer Is Revealed by Structure–Function Analysis

Ligumsky

Rubinek

Merenbakh-Lamin

et al. 2015

Molecular Cancer Research

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Klotho is a transmembrane protein containing two internal repeats, KL1 and KL2, both displaying significant homology to members of the b-glycosidase family. Klotho is expressed in the kidney, brain, and various endocrine tissues, but can also be cleaved and act as a circulating hormone. Klotho is an essential cofactor for binding of fibroblast growth factor 23 (FGF23) to the FGF receptor and can also inhibit the insulin-like growth factor-1 (IGF-1) pathway. Data from a wide array of malignancies indicate klotho as a tumor suppressor; however, the structure-function relationships governing its tumor suppressor activities have not been deciphered. Here, the tumor suppressor activities of the KL1 and KL2 domains were examined. Overexpression of either klotho or KL1, but not of KL2, inhibited colony formation by MCF-7 and MDA-MB-231 cells. Moreover, in vivo administration of KL1 was not only well tolerated but significantly slowed tumor formation in nude mice. Further studies indicated that KL1, but not KL2, interacted with the IGF-1R and inhibited the IGF-1 pathway. Based on computerized structural modeling, klotho constructs were generated in which critical amino acids have been mutated. Interestingly, the mutated proteins retained their tumor suppressor activity but showed reduced ability to modulate FGF23 signaling. These data indicate differential activity of the klotho domains, KL1 and KL2, in breast cancer and reveal that the tumor suppressor activities of klotho can be dissected from its physiologic activities.Implications: These findings pave the way for a rational design of safe klotho-based molecules for the treatment of breast cancer.

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“…The docking analysis was performed for Arg51Gln mutation as this particular amino acid lies in the mature ghrelin protein. Molecular modeling of wild and mutant ghrelin was carried out using easy modeler (Sali et al 1995). These were then octanoylated using AutoDock.…”

Section: In Silico Analysismentioning

confidence: 99%

Association of genetic variants of ghrelin, leptin and UCP2 with malnutrition inflammation syndrome and survival in end-stage renal disease patients

et al. 2013

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Evaluation of comparative protein modeling by MODELLER

Cited by 1,045 publications

References 36 publications

Side-chain and backbone flexibility in protein core design 1 1Edited by A. R. Fersht

Side-chain and backbone flexibility in protein core design 1 1Edited by A. R. Fersht

Tumor Suppressor Activity of Klotho in Breast Cancer Is Revealed by Structure–Function Analysis

Association of genetic variants of ghrelin, leptin and UCP2 with malnutrition inflammation syndrome and survival in end-stage renal disease patients

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