Design, synthesis and structure of a zinc finger with an artificial β-turn

Viles, John H.; Patel, Shelain; Mitchell, John B. O.; Moody, Claire M.; Justice, David; Uppenbrink, Julia; Doyle, Paul M.; Harris, Christopher; Sadler, Peter J.; Thornton, Janet M.

doi:10.1006/jmbi.1998.1764

Cited by 30 publications

(16 citation statements)

References 58 publications

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“…The resulting structure was further refined with RDC data after optimization of the parameters Da and Rh. The angle restraints of the zinc coordination geometry were based on ideal geometries derived from X-ray data 39,40 , which are in quantitative agreement with the EXAFS experiments. Distances derived from EXAFS have previously been used as restraints in NMR refinement 41,42 .…”

Section: Methodsmentioning

confidence: 73%

Structure and dynamics of a primordial catalytic fold generated by in vitro evolution

et al. 2012

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Engineering functional protein scaffolds capable of carrying out chemical catalysis is a major challenge in enzyme design. Starting from a non-catalytic protein scaffold, we recently generated a novel RNA ligase by in vitro directed evolution. This artificial enzyme lost its original fold and adopted an entirely novel structure with dramatically enhanced conformational dynamics, demonstrating that a primordial fold with suitable flexibility is sufficient to carry out enzymatic function.

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Section: Methodsmentioning

confidence: 73%

Structure and dynamics of a primordial catalytic fold generated by in vitro evolution

et al. 2012

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“…Compound 5, designed to replace the i ϩ 1 and i ϩ 2 residues of a type II ␤-turn (25), was expected to introduce a Pin WW twist preference mismatch. Although 1 has been incorporated into folded proteins (40,41), its influence on folding kinetics is unknown. ␤-Turn mimics 4 and 5 have been included in place of loop 1 residues in Pin WW as part of a study to discern the energetic requirements for the transition from two-state folding to downhill folding (38).…”

Section: Resultsmentioning

confidence: 99%

Evaluating β-turn mimics as β-sheet folding nucleators

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Liu

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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␤-Turns are common conformations that enable proteins to adopt globular structures, and their formation is often rate limiting for folding. ␤-Turn mimics, molecules that replace the i ؉ 1 and i ؉ 2 amino acid residues of a ␤-turn, are envisioned to act as folding nucleators by preorganizing the pendant polypeptide chains, thereby lowering the activation barrier for ␤-sheet formation. However, the crucial kinetic experiments to demonstrate that ␤-turn mimics can act as strong nucleators in the context of a cooperatively folding protein have not been reported. We have incorporated 6 ␤-turn mimics simulating varied ␤-turn types in place of 2 residues in an engineered ␤-turn 1 or ␤-bulge turn 1 of the Pin 1 WW domain, a three-stranded ␤-sheet protein. We present 2 lines of kinetic evidence that the inclusion of ␤-turn mimics alters ␤-sheet folding rates, enabling us to classify ␤-turn mimics into 3 categories: those that are weak nucleators but permit Pin WW folding, native-like nucleators, and strong nucleators. Strong nucleators accelerate folding relative to WW domains incorporating all ␣-amino acid sequences. A solution NMR structure reveals that the native Pin WW ␤-sheet structure is retained upon incorporating a strong E-olefin nucleator. These ␤-turn mimics can now be used to interrogate protein folding transition state structures and the 2 kinetic analyses presented can be used to assess the nucleation capacity of other ␤-turn mimics.beta-sheet nucleator ͉ kinetic assessment of turn mimics ͉ Pin WW domain ͉ protein folding

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“…The first C2H2 ZF of the C-terminal double ZF motif in SALL4 containing the studied mutation H888R was modeled from crystal structures of consensus sequences of homologous ZF domains (Houbaviy et al 1996;Miller and Pabo 2001;Narayan et al 1997;Viles et al 1998) using the human YY1 ZF (1UBD) (Houbaviy et al 1996) as a template. Model refinement and interaction energies were computed by molecular mechanics using CFF91 forcefield (Maple et al 1994).…”

Section: Molecular Modeling Methodsmentioning

confidence: 99%

A SALL4 zinc finger missense mutation predicted to result in increased DNA binding affinity is associated with cranial midline defects and mild features of Okihiro syndrome

et al. 2006

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Truncating mutations of the gene SALL4 on chromosome 20q13.13-13.2 cause Okihiro and acro-renal-ocular syndromes. Pathogenic missense mutations within the SALL4 or SALL1 genes have not yet been reported, raising the question which phenotypic features would be associated with them. Here we describe the first missense mutation within the SALL4 gene. The mutation results in an exchange of a highly conserved zinc-coordinating Histidine crucial for zinc finger (ZF) structure within a C2H2 double ZF domain to an Arginine. Molecular modeling predicts that this exchange does not result in a loss of zinc ion binding but leads to an increased DNA-binding affinity of the domain. The index patient shows mild features of Okihiro syndrome, but in addition cranial midline defects (pituitary hypoplasia and single central incisor). This finding illustrates that the phenotypic and functional effects of SALL4 missense mutations are difficult to predict, and that other SALL4 missense mutations might lead to phenotypes not overlapping with Okihiro syndrome.

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Design, synthesis and structure of a zinc finger with an artificial β-turn

Cited by 30 publications

References 58 publications

Structure and dynamics of a primordial catalytic fold generated by in vitro evolution

Structure and dynamics of a primordial catalytic fold generated by in vitro evolution

Evaluating β-turn mimics as β-sheet folding nucleators

A SALL4 zinc finger missense mutation predicted to result in increased DNA binding affinity is associated with cranial midline defects and mild features of Okihiro syndrome

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