9O5D

The KICSTOR-GATOR1-SAMTOR complex

Summary for 9O5D

• Entry DOI: 10.2210/pdb9o5d/pdb
• Related: 9O5A
• EMDB information: 70135 70140
• Descriptor: GATOR complex protein NPRL2, GATOR1 complex protein DEPDC5, S-adenosylmethionine sensor upstream of mTORC1, ... (5 entities in total)
• Functional Keywords: lysosome, gator1, kicstor, cell growth, amino acid sensing, mtor, kptn, itfg2, c12orf66, szt2, nprl2, nprl3, depdc5, cell cycle
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 5
• Total formula weight: 491763.89

Authors

Bayly-Jones, C.,Lupton, C.J.,Chang, Y.G.,Ellisdon, A.M. (deposition date: 2025-04-10, release date: 2026-01-21)

Primary citation

Lupton, C.J.,Bayly-Jones, C.,Dong, S.,Lam, T.,Luo, W.,Jones, G.D.,Mastos, C.,Frescher, N.J.,Lim, S.S.,Keen, A.C.,Formosa, L.E.,Venugopal, H.,Chang, Y.G.,Halls, M.L.,Ellisdon, A.M.
Structure of the lysosomal KICSTOR-GATOR1-SAMTOR nutrient-sensing supercomplex.
Cell, 2026

PubMed Abstract: The guanosine triphosphate (GTP)-bound state of the heterodimeric Rag GTPases functions as a molecular switch regulating mechanistic target of rapamycin complex 1 (mTORC1) activation at the lysosome downstream of amino acid fluctuations. Under low amino acid conditions, GTPase-activating protein (GAP) activity toward Rags 1 (GATOR1) promotes RagA GTP hydrolysis, preventing mTORC1 activation. KICSTOR recruits and regulates GATOR1 at the lysosome by undefined mechanisms. Here, we resolve the KICSTOR-GATOR1 structure, revealing a striking ∼60-nm crescent-shaped assembly. GATOR1 anchors to KICSTOR via an extensive interface, and mutations that disrupt this interaction impair mTORC1 regulation. The S-adenosylmethionine sensor SAMTOR binds KICSTOR in a manner incompatible with metabolite binding, providing structural insight into methionine sensing via SAMTOR-KICSTOR association. We discover that KICSTOR and GATOR1 form a dimeric supercomplex. This assembly restricts GATOR1 to an orientation that favors the low-affinity active GAP mode of Rag GTPase engagement while sterically restricting access to the high-affinity inhibitory mode, consistent with a model of an active lysosomal GATOR1 docking complex.

PubMed: 41512879
DOI: 10.1016/j.cell.2025.12.005

Experimental method

ELECTRON MICROSCOPY (3.34 Å)