9OJ4

Mouse LRRC15 extracellular domain in complex with disulfide constrained peptide ML-YSD-07 and Fab-E1

Summary for 9OJ4

• Entry DOI: 10.2210/pdb9oj4/pdb
• Related: 9OIB
• Descriptor: Fab-E1 light chain, Fab-E1 heavy chain, Leucine-rich repeat-containing protein 15, ... (7 entities in total)
• Functional Keywords: leucine-rich repeat, disulfide constrained peptide, fab, signaling protein, signaling protein-immune system complex, signaling protein/immune system
• Biological source: Homo sapiens; More
• Total number of polymer chains: 4
• Total formula weight: 103211.94

Authors

Wendorff, T.J.,Tombling, B. (deposition date: 2025-05-07, release date: 2026-05-13, Last modification date: 2026-07-22)

Primary citation

Tombling, B.J.,Cai, F.,Wendorff, T.J.,Ogasawara, A.,Gill, H.S.,Tinianow, J.N.,Chang, A.,Balana, A.T.,Peng, L.,Miller, S.E.,Walters, B.T.,Lictao, A.,Yu, Q.,DeWitt, D.C.,Wei, Y.,Wu, S.Z.,Sudhamsu, J.,Krishnamurty, A.T.,Williams, S.P.,Marik, J.,Zhang, Y.,Maun, H.R.,Kirchhofer, D.
Development of LRRC15-binding disulfide-constrained peptides for PET imaging of cancer-associated fibroblasts.
Nat Commun, 17:-, 2026

PubMed Abstract: Leucine-rich-repeat-containing protein 15 (LRRC15) is selectively expressed on cancer-associated fibroblasts (CAFs) and constitutes a promising biomarker for imaging the tumor microenvironment. Using a combinatorial library approach, assisted by machine learning, we developed disulfide-constrained peptides (DCPs), notably ML-YSD-07 and ML-PD-03, that demonstrate subnanomolar affinities for murine LRRC15 (muLRRC15) and specifically localize onto muLRRC15-expressing fibroblasts. PET imaging with F-radiolabeled ML-YSD-07 exhibits specific tumor accumulation in a murine pancreatic cancer model highly enriched with LRRC15-expressing CAFs. Crystal structures of apo-muLRRC15 and of ML-YSD-07-bound muLRRC15 show that the DCPs evolved to adopt a distinct binding conformation that efficiently interacts with a flat epitope on muLRRC15. Collectively, this work identifies potent, molecularly engineered LRRC15-binding peptides and further highlights LRRC15 as a valuable CAF biomarker for cancer imaging applications.

PubMed: 42248838
DOI: 10.1038/s41467-026-73845-z

Experimental method

X-RAY DIFFRACTION (2.57 Å)