Nonnatural protein–protein interaction-pair design by key residues grafting

Liu, Sen; Liu, Shiyong; Zhu, Xiaolei; Liang, Huanhuan; Cao, Aoneng; Chen, Zhijie; Lai, Luhua

doi:10.1073/pnas.0606198104

Cited by 75 publications

(60 citation statements)

References 48 publications

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“…Thus far, most computational designs of new interactions have involved either the pairing of α-helices (3-6) or binding of an α-helix to an open groove on a target (7-10). Other methodologies have focused on grafting side-chain interactions from a known interaction onto another scaffold (7,11,12). There have been two examples of structurally confirmed unique computational interface designs (6, 7), however these sample a limited set of modes by which proteins can interact.…”

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confidence: 99%

Computational design of a symmetric homodimer using β-strand assembly

Stranges

Machius

Miley

et al. 2011

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

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Computational design of novel protein-protein interfaces is a test of our understanding of protein interactions and has the potential to allow modification of cellular physiology. Methods for designing high-affinity interactions that adopt a predetermined binding mode have proved elusive, suggesting the need for new strategies that simplify the design process. A solvent-exposed backbone on a β-strand is thought of as "sticky" and β-strand pairing stabilizes many naturally occurring protein complexes. Here, we computationally redesign a monomeric protein to form a symmetric homodimer by pairing exposed β-strands to form an intermolecular β-sheet. A crystal structure of the designed complex closely matches the computational model (rmsd 1.0 Å). This work demonstrates that β-strand pairing can be used to computationally design new interactions with high accuracy.computational protein design | protein design | protein interface design | Rosetta P rotein-protein interactions and assemblies are essential for a wide array of cellular processes. The ability to rationally design unique protein interactions could provide scaffolds for functional reactions and new reagents for perturbing and monitoring cellular processes. Computational approaches for interface design have advanced rapidly in recent years and have allowed interactions to be engineered for increased affinity or altered specificity (1, 2). One long-standing goal is the creation of unique interactions. Thus far, most computational designs of new interactions have involved either the pairing of α-helices (3-6) or binding of an α-helix to an open groove on a target (7-10). Other methodologies have focused on grafting side-chain interactions from a known interaction onto another scaffold (7,11,12). There have been two examples of structurally confirmed unique computational interface designs (6, 7), however these sample a limited set of modes by which proteins can interact. New methods of constructing an interface are necessary to mimic the ways nature forms protein-protein interactions (13).There are many examples of naturally occurring protein heterodimers, homodimers, and larger complexes where β-strands from each chain associate to form an intermolecular β-sheet (14); β-strand pairing has also been observed in evolved antibody-antigen interactions (15) and monobody-target interfaces selected from phage display libraries (16). It has been proposed that β-strand pairing is so favorable that naturally occurring proteins often use negative design to avoid edge-to-edge association. In one study, 75 monomeric β-sheet proteins were visually examined to see if they contained structural features that would be predicted to disfavor β-sheet formation across their edge strands (17). In almost every case, one or more negative design elements were present including prolines, strategically placed charges, very short edge strands, loop coverage, and irregular edge strands. The propensity of exposed β-strands to pair is reinforced by observations of intermolecular β-sheet forma...

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confidence: 99%

Computational design of a symmetric homodimer using β-strand assembly

Stranges

Machius

Miley

et al. 2011

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

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“…This method can be used to discover new protein scaffolds that can accommodate the enzyme reaction and has already been successfully used for protein-protein interface design. 11 As enzyme catalytic reactions also involve key residues, a similar approach can be applied for enzyme design. Efficient enzyme catalysis depends on the local microstructure of the binding site: not only the accurate orientation of active residues, but also the distribution of other cavity residues.…”

Section: Discussionmentioning

confidence: 99%

“…This approach has been successfully applied in protein-protein interface design. 11 To test this strategy for enzyme design, we used triose phosphate isomerase as a design target.…”

Section: Introductionmentioning

confidence: 99%

A novel method for enzyme design

Zhu

Lai

2008

J Comput Chem

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Rational design of enzymes is a stringent test of our understanding of protein structure and function relationship, which also has numerous potential applications. We present a novel method for enzyme design that can find good candidate protein scaffolds in a protein-ligand database based on vector matching of key residues. Residues in the vicinity of the active site were also compared according to a similarity score between the scaffold protein and the target enzyme. Suitable scaffold proteins were selected, and the side chains of residues around the active sites were rebuilt using a previously developed side-chain packing program. Triose phosphate isomerase (TIM) was used as a validation test for enzyme design. Selected scaffold proteins were found to accommodate the enzyme active sites and successfully form a good transition state complex. This method overcomes the limitations of the current enzyme design methods that use limited number of protein scaffold and based on the position of ligands. As there are a large number of protein scaffolds available in the Protein Data Band, this method should be widely applicable for various types of enzyme design.

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“…Naturally this has the limitation that we must have already seen an interaction of the type we need, however it is an approach, which has been shown to work. Liu et al [58] demonstrated this with the human erythropoietin receptor and the pleckstrin homology domain of rat phospholipase D (PLCd1-PH). By scanning the PDB with the key residues from the human erythropoietin (EPO)-EPO receptor (erythropoietin receptor EPO) binding site, the binding site of the PLCd1-PH was identified as a suitable target for grafting.…”

Section: Design Of Protein Interfacesmentioning

confidence: 99%