Evidence map›Paper›PMID 40894751›Full record

ArticlebioRxiv : the preprint server for biology2025

Time-Resolved Crystallography Reveals the Mechanisms of GTP hydrolysis for N-RAS and the Oncogenic Mutants G12C, G12V and Q61L.

Guowu Lin, Paola Zinser-Peniche, Xiaohong Zhou, Ulises Santiago, Igor Kurnikov, Silvia Russi, Brisa Chagas, May E Sharpe, Dennis P Stegmann, Shannon A Heinig and 9 more

Abstract readPreprint
PubMed Full text at PMC Publisher
In one paragraph

Article in bioRxiv : the preprint server for biology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.

0numbers the graph read from it
0cells of the map it votes in
2citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

2 citing papers in PubMed.

  1. Review
  2. Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

19 authors.

Guowu LinDepartment of Structural Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Paola Zinser-PenicheDepartment of Structural Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Xiaohong ZhouDepartment of Structural Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Ulises SantiagoDepartment of Structural Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Igor KurnikovDepartment of Chemistry, Carnegie Mellon University, Pittsburgh, PA, USA.
Silvia RussiStanford Synchrotron Radiation Lightsource, SLAC National Accelerator Laboratory, Stanford University, Menlo Park, CA, USA.
Brisa ChagasDepartment of Structural Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
May E SharpeSwiss Light Source, Paul Scherrer Institute, Villigen, Switzerland.
Dennis P StegmannSwiss Light Source, Paul Scherrer Institute, Villigen, Switzerland.
Shannon A HeinigUPMC Hillman Cancer Center, Pittsburgh, PA, USA.
Rohan K GoyalUPMC Hillman Cancer Center, Pittsburgh, PA, USA.
V NagarajanJAN Scientific Inc., Seattle, WA, USA.
Daniel CaleroDepartment of Structural Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Sandra VergaraDepartment of Structural Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Alexander DeitersDepartment of Chemistry, University of Pittsburgh. Pittsburgh PA, USA.
Maria G KurnikovaDepartment of Chemistry, Carnegie Mellon University, Pittsburgh, PA, USA.
Timothy F BurnsUPMC Hillman Cancer Center, Pittsburgh, PA, USA.
Aina CohenStanford Synchrotron Radiation Lightsource, SLAC National Accelerator Laboratory, Stanford University, Menlo Park, CA, USA.
Guillermo CaleroDepartment of Structural Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

The RAS family of small GTPases are molecular switches that convey downstream signals regulating cell proliferation, differentiation, and apoptosis. The signaling competent GTP-bound RAS transitions to its inactive GDP-bound form through γ-phosphate hydrolysis. Oncogenic RAS mutations hamper GTP hydrolysis and are present in up to 30% of all human cancers. Structural studies of RAS proteins bound to non-hydrolysable GTP analogs have revealed snapshots of the enzyme in its possibly active form. Yet, the mechanism of GTP hydrolysis has not been structurally resolved. To visualize this reaction in real time, we performed time-resolved crystallographic experiments employing a photolabile caged-GTP substrate. Fifty-seven distinctive reaction intermediates were captured during hydrolysis of a live GTP for N-RAS, the oncogenic mutants G12C, G12V and Q61L; and Y32R, a fast hydrolytic mutant. The reaction mechanisms and rates for the native and each of the mutants differed significantly; however, they shared common elements: an initially catalytically-defective open state, which transitions into the closed Michaelis complex state with solvent-assisted O3B-Pγ bond lengthening and breaking, followed by the release of the Mg

Identifiers

PMID40894751
PMCPMC12393572

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.