Size versus polarizability in protein-ligand interactions: binding of noble gases within engineered cavities in phage T4 lysozyme

Quillin, M.L.; Breyer, Wendy A.; Griswold, Ian J.; Matthews, Brian W.

doi:10.1006/jmbi.2000.4063

Cited by 116 publications

(166 citation statements)

References 89 publications

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“…Importantly, xenon also possesses an appreciable anomalous signal, allowing for unambiguous localization of xenon atoms in protein crystal structures (34). Although xenon has high polarizability, which can bias interactions toward regions in proteins with more polarizable side chains (36), numerous studies have confirmed that the locations of xenon binding sites correlate well with areas that are favorable for diatomic gas migration (12,13).…”

Section: Resultsmentioning

confidence: 99%

Tunnels modulate ligand flux in a heme nitric oxide/oxygen binding (H-NOX) domain

Winter

Herzik

Kuriyan

et al. 2011

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

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Interior topological features, such as pockets and channels, have evolved in proteins to regulate biological functions by facilitating the diffusion of biomolecules. Decades of research using the globins as model heme proteins have clearly highlighted the importance of gas pockets around the heme in controlling the capture and release of O 2 . However, much less is known about how ligand migration contributes to the diverse functions of other heme protein scaffolds. Heme nitric oxide/oxygen binding (H-NOX) domains are a conserved family of gas-sensing heme proteins with a divergent fold that are critical to numerous signaling pathways. Utilizing X-ray crystallography with xenon, a tunnel network has been shown to serve as a molecular pathway for ligand diffusion. Structure-guided mutagenesis results show that the tunnels have unexpected effects on gas-sensing properties in H-NOX domains. The findings provide insights on how the flux of biomolecules through protein scaffolds modulates protein chemistry.

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Section: Resultsmentioning

confidence: 99%

Tunnels modulate ligand flux in a heme nitric oxide/oxygen binding (H-NOX) domain

Winter

Herzik

Kuriyan

et al. 2011

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

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“…The Leu-99 3 Ala mutation creates a large cavity that destabilizes the folded protein because of lost interactions between side chains and the reduced free-energy cost of exposing alanine (instead of leucine) to water (17). L99A T4 lysozyme has also been the subject of ligand-and noble-gas-binding studies (18)(19)(20) and is believed to be entirely empty under ambient conditions. Under pressure, one may expect a large cavity, similar to that produced by the L99A mutation, to collapse.…”

mentioning

confidence: 99%

Cooperative water filling of a nonpolar protein cavity observed by high-pressure crystallography and simulation

Collins

Hummer

Quillin

et al. 2005

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

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Formation of a water-expelling nonpolar core is the paradigm of protein folding and stability. Although experiment largely confirms this picture, water buried in “hydrophobic” cavities is required for the function of some proteins. Hydration of the protein core has also been suggested as the mechanism of pressure-induced unfolding. We therefore are led to ask whether even the most nonpolar protein core is truly hydrophobic (i.e., water-repelling). To answer this question we probed the hydration of an ≈160-Å 3 , highly hydrophobic cavity created by mutation in T4 lysozyme by using high-pressure crystallography and molecular dynamics simulation. We show that application of modest pressure causes approximately four water molecules to enter the cavity while the protein itself remains essentially unchanged. The highly cooperative filling is primarily due to a small change in bulk water activity, which implies that changing solvent conditions or, equivalently, cavity polarity can dramatically affect interior hydration of proteins and thereby influence both protein activity and folding.

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“…enzyme specificities, creating novel binding sites, and studying protein stability (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12), but despite the diverse roles of natural cavities in biology, high-resolution structural investigations of model cavities in the aqueous milieu are rare. We believe studying designed cavities within synthetic peptides may provide models for understanding natural binding sites as well as designing novel receptors or biocatalysts.…”

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confidence: 99%

Structure-Based Engineering of Internal Cavities in Coiled-Coil Peptides^,

et al. 2005

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Cavities and clefts are frequently important sites of interaction between natural enzymes or receptors with their corresponding substrate or ligand molecules and exemplify the types of molecular surfaces that would facilitate engineering artificial catalysts and receptors. Even so, structural characterizations of designed cavities are rare. To address this issue, we performed a systematic study of the structural effects of single amino acid substitutions within the hydrophobic cores of tetrameric coiled-coil peptides. Peptides containing single glycine, serine, alanine, or threonine amino acid substitutions at the buried L9, L16, L23, and I26 hydrophobic core positions of a GCN4-based sequence were synthesized and studied by solution-phase and crystallographic techniques. All peptides adopt the expected tetrameric state and contain tunnels or internal cavities ranging in size from 80 Å 3 to 370 Å 3 . Two closely-related sequences containing an L16G substitution, one of which adopts an antiparallel configuration and one of which adopts a parallel configuration, illustrate that cavities of different volumes and shapes can be engineered from identical core substitutions. Finally, we demonstrate that two of the peptides (L9G and L9A) bind the small molecule iodobenzene when present during crystallization, leaving the general peptide quaternary structure intact but altering the local peptide conformation and certain superhelical parameters. These high-resolution descriptions of varied molecular surfaces within solvent-occluded internal cavities illustrate the breadth of design space available in even closely-related peptides and offer valuable models for the engineering of de novo helical proteins.A significant challenge frustrating the de novo design of functional molecules is that of precisely constructing molecular surfaces able to suitably participate in desired molecular recognition events. Internal cavities, relatively buried clefts, and tunnels are frequently important sites of interaction between natural enzymes or receptors with their corresponding substrate or ligand molecules, and the ability to engineer such surfaces would facilitate the successful design of highly-selective artificial catalysts and receptors. Mutagenesis of natural proteins to create or alter internal cavities has been used for such purposes as redesigning † We thank the National Institutes of Health for financial support (GM52190). JER, JMAG, and LJL thank the Wellcome Trust (061454/ Z/00/Z), the Spanish MCYT, and NSF, respectively, for fellowships. § Coordinates have been deposited in the RCSB Protein Data Bank: GCN4-pLI, 1UO2; L9G, 1UO3; L9S, 1UNU; L9A, 1UNT; L9T, 1UNV; L9G+IB, 1UO4; L9A+IB, 1UO5; L23G, 1UNW; L23S 1UNX; I26G, 1UNY; I26S, 1UNZ; I26A, 1UN0; I26T, 1UN1; L16G E20C, 1W5I; L16G E20C Y17H, 2BNI.* Address correspondence to this author. (858) 784-2700 (phone); (858) 784-2798 (fax); ghadiri@scripps.edu (e-mail).. 1 Abbreviations: CD, circular dichroism; SEC, size exclusion chromatography; ABA, acetamidobenzoic acid; MW,...

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Size versus polarizability in protein-ligand interactions: binding of noble gases within engineered cavities in phage T4 lysozyme

Cited by 116 publications

References 89 publications

Tunnels modulate ligand flux in a heme nitric oxide/oxygen binding (H-NOX) domain

Tunnels modulate ligand flux in a heme nitric oxide/oxygen binding (H-NOX) domain

Cooperative water filling of a nonpolar protein cavity observed by high-pressure crystallography and simulation

Structure-Based Engineering of Internal Cavities in Coiled-Coil Peptides^,

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Size versus polarizability in protein-ligand interactions: binding of noble gases within engineered cavities in phage T4 lysozyme

Cited by 116 publications

References 89 publications

Tunnels modulate ligand flux in a heme nitric oxide/oxygen binding (H-NOX) domain

Tunnels modulate ligand flux in a heme nitric oxide/oxygen binding (H-NOX) domain

Cooperative water filling of a nonpolar protein cavity observed by high-pressure crystallography and simulation

Structure-Based Engineering of Internal Cavities in Coiled-Coil Peptides,

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Structure-Based Engineering of Internal Cavities in Coiled-Coil Peptides^,