ArticleProceedings of the National Academy of Sciences of the United States of America2016
Structural basis of recognition of farnesylated and methylated KRAS4b by PDEδ.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 107 papers.
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Who cites it
107 citing papers in PubMed, 172 citations in OpenAlex.
- Regulation of Membrane Association and Downstream Effector Interaction of K-Ras by Its Hypervariable Region.Membranes · 2026Article
- High yield production of C-terminally processed KRAS4a, HRAS, and NRAS for biophysical study.Protein expression and purification · 2026Article
- K-Ras controls asymmetric cell divisions from the primary cilium.Cell death & disease · 2026Article
- Biochemical Mechanisms of Phosphodiesterase 6D Inhibition in K-Ras-Driven Cancers.Applied biochemistry and biotechnology · 2026Article
- α-Halothioamide warheads with enhanced cysteine reactivity and specificity for covalent protein labelling.Nature communications · 2026Article
- Protein farnesylation: from molecular mechanisms to therapeutic targeting in cancer, aging, and beyond.Frontiers in pharmacology · 2026Review
- Development of a Genetically Encoded and Potent PDE6D Inhibitor.Chembiochem : a European journal of chemical biology · 2025Article
- Structural basis for LZTR1 recognition of RAS GTPases for degradation.Science (New York, N.Y.) · 2025Article
- RAS-membrane interaction and oligomerization: there is more than meets the eye.Biochemical Society transactions · 2025Review
- Drugging Ras trafficking-are there new roads to travel?npj drug discovery · 2025Review
- Blocking C-terminal processing of KRAS4b via a direct covalent attack on the CaaX-box cysteine.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Targeting KRAS: from metabolic regulation to cancer treatment.Molecular cancer · 2025Review
- KRas4b-Calmodulin Interaction with Membrane Surfaces: Role of Headgroup, Acyl Chain, and Electrostatics.Biochemistry · 2024Article
- Comprehensive structure-function analysis reveals gain- and loss-of-function mechanisms impacting oncogenic KRAS activity.bioRxiv : the preprint server for biology · 2024Article
- KRAS-Driven Tumorigenesis and KRAS-Driven Therapy in Pancreatic Adenocarcinoma.Molecular cancer therapeutics · 2024Review
- Differential Lipid Binding Specificities of RAP1A and RAP1B are Encoded by the Amino Acid Sequence of the Membrane Anchors.Journal of the American Chemical Society · 2024Article
- An Improved PDE6D Inhibitor Combines with Sildenafil To InhibitJournal of medicinal chemistry · 2024Article
- A Top-Down Proteomic Assay to Evaluate KRAS4B-Compound Engagement.Analytical chemistry · 2024Article
- Protein lipidation in health and disease: molecular basis, physiological function and pathological implication.Signal transduction and targeted therapy · 2024Review
- Comparative analysis of KRAS4a and KRAS4b splice variants reveals distinctive structural and functional properties.Science advances · 2024Article
47 more citing papers are in PubMed but not listed here.
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Authors and funding
11 authors at 5 institutions in 1 country.
Funding
Abstract
Farnesylation and carboxymethylation of KRAS4b (Kirsten rat sarcoma isoform 4b) are essential for its interaction with the plasma membrane where KRAS-mediated signaling events occur. Phosphodiesterase-δ (PDEδ) binds to KRAS4b and plays an important role in targeting it to cellular membranes. We solved structures of human farnesylated-methylated KRAS4b in complex with PDEδ in two different crystal forms. In these structures, the interaction is driven by the C-terminal amino acids together with the farnesylated and methylated C185 of KRAS4b that binds tightly in the central hydrophobic pocket present in PDEδ. In crystal form II, we see the full-length structure of farnesylated-methylated KRAS4b, including the hypervariable region. Crystal form I reveals structural details of farnesylated-methylated KRAS4b binding to PDEδ, and crystal form II suggests the potential binding mode of geranylgeranylated-methylated KRAS4b to PDEδ. We identified a 5-aa-long sequence motif (Lys-Ser-Lys-Thr-Lys) in KRAS4b that may enable PDEδ to bind both forms of prenylated KRAS4b. Structure and sequence analysis of various prenylated proteins that have been previously tested for binding to PDEδ provides a rationale for why some prenylated proteins, such as KRAS4a, RalA, RalB, and Rac1, do not bind to PDEδ. Comparison of all four available structures of PDEδ complexed with various prenylated proteins/peptides shows the presence of additional interactions due to a larger protein-protein interaction interface in KRAS4b-PDEδ complex. This interface might be exploited for designing an inhibitor with minimal off-target effects.
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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.