Oncogenic PI3Kα variants reveal graded conformational spectrum with mutation-specific cryptic pockets.

Hyunbum Jang, Bengi Ruken Yavuz, Mingzhen Zhang, Yonglan Liu, Ruth Nussinov

Abstract read

In one paragraph

Article in Communications chemistry, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

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0citing papers in PubMed

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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

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3 · Its place in the literature

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No citing paper in PubMed yet.

4 · The record

Corrections and comments

Update of
Oncogenic PI3Kα variants reveal graded conformational spectrum with mutation-specific cryptic pockets.2025

5 · Who and what money

Authors and funding

5 authors.

Hyunbum JangComputational Structural Biology Section, Frederick National Laboratory for Cancer Research, Frederick, MD, USA.ORCID http://orcid.org/0000-0001-9402-4051

Bengi Ruken YavuzCancer Innovation Laboratory, National Cancer Institute at Frederick, Frederick, MD, USA.ORCID http://orcid.org/0000-0002-3472-8767

Mingzhen ZhangComputational Structural Biology Section, Frederick National Laboratory for Cancer Research, Frederick, MD, USA.

Yonglan LiuCancer Innovation Laboratory, National Cancer Institute at Frederick, Frederick, MD, USA.

Ruth NussinovComputational Structural Biology Section, Frederick National Laboratory for Cancer Research, Frederick, MD, USA. NussinoR@mail.nih.gov.ORCID http://orcid.org/0000-0002-8115-6415

Funding

NCI NIH HHS HHSN261201500003I

6 · The paper itself

Abstract

Cancer-prone alleles exhibit single hotspot mutations. However, the combination of a cancer hotspot and a weak or moderate mutation (the 'one-two punch' hypothesis) produces same-allele double variants with a significantly different and potentially graded clinical phenotypic spectrum. Oncogenic PI3Kα variants, which are also associated with benign tumors and neurodevelopmental disorders, offer statistical support for this model. Using atomistic molecular dynamics (MD) simulations, we revealed that PI3Kα variants with single and double mutations exhibit expanded conformational profiles. Double mutations significantly shift the conformational ensembles toward the active form-a more pronounced effect than a single mutation. These double mutants facilitate nSH2 release, iSH2 shift, and A-loop protrusion in solution, promoting PIP

Identifiers

PMID41565991

DOI10.1038/s42004-026-01906-x

PMCPMC12923765

What Socratic holds

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LicenceCC BY

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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 Socratic graph.