Refined crystal structure of the triphosphate conformation of H-ras p21 at 1.35 A resolution: implications for the mechanism of GTP hydrolysis.

Pai, Emil F.; Krengel, Ute; Petsko, Gregory A.; Goody, Roger S.; Kabsch, Wolfgang; Wittinghofer, Alfred

doi:10.1002/j.1460-2075.1990.tb07409.x

Cited by 1,100 publications

(1,198 citation statements)

References 54 publications

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“…b) GTP analogue GppNp bound by hydrogen bonds from five consecutive main‐chain amides in a nest formation (PDB 5P2156). c) Simplified illustration of the C α NN motif.…”

Section: Macromolecular Recognition Of Anions In Watermentioning

confidence: 99%

Anion Recognition in Water: Recent Advances from a Supramolecular and Macromolecular Perspective

2015

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The recognition of anions in water remains a key challenge in modern supramolecular chemistry, and is essential if proposed applications in biological, medical, and environmental arenas that typically require aqueous conditions are to be achieved. However, synthetic anion receptors that operate in water have, in general, been the exception rather than the norm to date. Nevertheless, a significant step change towards routinely conducting anion recognition in water has been achieved in the past few years, and this Review highlights these approaches, with particular focus on controlling and using the hydrophobic effect, as well as more exotic interactions such as C−H hydrogen bonding and halogen bonding. We also look beyond the field of small‐molecule recognition into the macromolecular domain, covering recent advances in anion recognition based on biomolecules, polymers, and nanoparticles.

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“…b) GTP analogue GppNp bound by hydrogen bonds from five consecutive main‐chain amides in a nest formation (PDB 5P2156). c) Simplified illustration of the C α NN motif.…”

Section: Macromolecular Recognition Of Anions In Watermentioning

confidence: 99%

Anion Recognition in Water: Recent Advances from a Supramolecular and Macromolecular Perspective

2015

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“…Since the HisP protein was crystallized in a Mg 2+ -free environment we can only speculate about the position of the cofactor. However, one of the waters mediating the interaction between the Walker B motif and the γ-phosphate is found in a similar position to the magnesium ion in the structure of Ras-GMP-PNP-Mg 2+ (Pai et al 1990) and thus suggests a possible position for the cofactor in HisP. Two more water mediated interactions are noteworthy.…”

Section: Conformation Of the Monomermentioning

confidence: 91%

The motor domains of ABC-transporters

Oswald

Holland

Schmitt

2006

Naunyn Schmied Arch Pharmacol

130

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The transport of substrates across a cellular membrane is a vitally important biological function essential for cell survival. ATP-binding cassette (ABC) transporters constitute one of the largest subfamilies of membrane proteins, accomplishing this task. Mutations in genes encoding for ABC transporters cause different diseases, for example, Adrenoleukodystrophy, Stargardt disease or Cystic Fibrosis. Furthermore, some ABC transporters are responsible for multidrug resistance, presenting a major obstacle in modern cancer chemotherapy. In order to translocate the enormous variety of substrates, ranging from ions, nutrients, small peptides to large toxins, different ABC-transporters utilize the energy gained from ATP binding and hydrolysis. The ATP binding cassette, also called the motor domain of ABC transporters, is highly conserved among all ABC transporters. The ability to purify this domain rather easily presents a perfect possibility to investigate the mechanism of ATP hydrolysis, thus providing us with a detailed picture of this process. Recently, many crystal structures of the ATP-binding domain and the full-length structures of two ABC transporters have been solved. Combining these structural data, we have now the opportunity to analyze the hydrolysis event on a molecular level. This review provides an overview of the structural investigations of the ATPbinding domains, highlighting molecular changes upon ATP binding and hydrolysis.

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“…Structural studies, mutational experiments and the use of TS analogs have proven unable to elucidate the origin of the catalytic role of Gln 61 . In fact, all early works (e.g., Krengel et al 1990 ;Pai et al 1990) concluded that glutamine must be crucial as a general base that extracts a proton from the nucleophilic water molecule. This view was drastically changed by our study (Langen et al 1992), in which we demonstrated that Gln 61 cannot be the general base in Ras (since the energy of the proposed PT step in Ras is higher than the actual observed barrier for the GTPase reaction in solution).…”

Section: The Ras/gap System and The Mechanism Of The Corresponding Phmentioning

confidence: 99%

Why nature really chose phosphate

Kamerlin

Sharma

Prasad

et al. 2013

Quart. Rev. Biophys.

318

435

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Phosphoryl transfer plays key roles in signaling, energy transduction, protein synthesis, and maintaining the integrity of the genetic material. On the surface, it would appear to be a simple nucleophile displacement reaction. However, this simplicity is deceptive, as, even in aqueous solution, the low-lying d-orbitals on the phosphorus atom allow for eight distinct mechanistic possibilities, before even introducing the complexities of the enzyme catalyzed reactions. To further complicate matters, while powerful, traditional experimental techniques such as the use of linear free-energy relationships (LFER) or measuring isotope effects cannot make unique distinctions between different potential mechanisms. A quarter of a century has passed since Westheimer wrote his seminal review, ‘Why Nature Chose Phosphate’ (Science 235 (1987), 1173), and a lot has changed in the field since then. The present review revisits this biologically crucial issue, exploring both relevant enzymatic systems as well as the corresponding chemistry in aqueous solution, and demonstrating that the only way key questions in this field are likely to be resolved is through careful theoretical studies (which of course should be able to reproduce all relevant experimental data). Finally, we demonstrate that the reason that naturereallychose phosphate is due to interplay between two counteracting effects: on the one hand, phosphates are negatively charged and the resulting charge-charge repulsion with the attacking nucleophile contributes to the very high barrier for hydrolysis, making phosphate esters among the most inert compounds known. However, biology is not only about reducing the barrier to unfavorable chemical reactions. That is, the same charge-charge repulsion that makes phosphate ester hydrolysis so unfavorable also makes it possible to regulate, by exploiting the electrostatics. This means that phosphate ester hydrolysis can not only be turned on, but also be turned off, by fine tuning the electrostatic environment and the present review demonstrates numerous examples where this is the case. Without this capacity for regulation, it would be impossible to have for instance a signaling or metabolic cascade, where the action of each participant is determined by the fine-tuned activity of the previous piece in the production line. This makes phosphate esters the ideal compounds to facilitate life as we know it.

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Refined crystal structure of the triphosphate conformation of H-ras p21 at 1.35 A resolution: implications for the mechanism of GTP hydrolysis.

Cited by 1,100 publications

References 54 publications

Anion Recognition in Water: Recent Advances from a Supramolecular and Macromolecular Perspective

Anion Recognition in Water: Recent Advances from a Supramolecular and Macromolecular Perspective

The motor domains of ABC-transporters

Why nature really chose phosphate

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