8T74

Crystal structure of KRAS4a (GMPPNP) in complex with RAF1 (RBD)

Summary for 8T74

• Entry DOI: 10.2210/pdb8t74/pdb
• Descriptor: GTPase KRas, RAF proto-oncogene serine/threonine-protein kinase, MAGNESIUM ION, ... (5 entities in total)
• Functional Keywords: ras, kras, raf1, craf, oncoprotein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 30079.27

Authors

Whitley, M.J.,Simanshu, D.K. (deposition date: 2023-06-19, release date: 2024-02-14, Last modification date: 2024-02-28)

Primary citation

Whitley, M.J.,Tran, T.H.,Rigby, M.,Yi, M.,Dharmaiah, S.,Waybright, T.J.,Ramakrishnan, N.,Perkins, S.,Taylor, T.,Messing, S.,Esposito, D.,Nissley, D.V.,McCormick, F.,Stephen, A.G.,Turbyville, T.,Cornilescu, G.,Simanshu, D.K.
Comparative analysis of KRAS4a and KRAS4b splice variants reveals distinctive structural and functional properties.
Sci Adv, 10:eadj4137-eadj4137, 2024

PubMed Abstract: , the most frequently mutated oncogene in human cancer, produces two isoforms, KRAS4a and KRAS4b, through alternative splicing. These isoforms differ in exon 4, which encodes the final 15 residues of the G-domain and hypervariable regions (HVRs), vital for trafficking and membrane localization. While KRAS4b has been extensively studied, KRAS4a has been largely overlooked. Our multidisciplinary study compared the structural and functional characteristics of KRAS4a and KRAS4b, revealing distinct structural properties and thermal stability. Position 151 influences KRAS4a's thermal stability, while position 153 affects binding to RAF1 CRD protein. Nuclear magnetic resonance analysis identified localized structural differences near sequence variations and provided a solution-state conformational ensemble. Notably, exhibits substantial transcript abundance in bile ducts, liver, and stomach, with transcript levels approaching in the colon and rectum. Functional disparities were observed in full-length KRAS variants, highlighting the impact of HVR variations on interaction with trafficking proteins and downstream effectors like RAF and PI3K within cells.

PubMed: 38354232
DOI: 10.1126/sciadv.adj4137

Experimental method

X-RAY DIFFRACTION (1.65 Å)