37UU

Cryo-EM structure of human Fibroblast Activation Protein alpha in complex with F7 VHH

Summary for 37UU

• Entry DOI: 10.2210/pdb37uu/pdb
• Related: 37US 37UT
• EMDB information: 78501 78502 78503
• Descriptor: F7 VHH-human IgG1 Fc fusion protein, Fibroblast activation protein alpha, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (4 entities in total)
• Functional Keywords: fibroblast activation protein alpha, f7, single-domain antibody, vhh, hydrolase
• Biological source: Camelidae; More
• Total number of polymer chains: 4
• Total formula weight: 257186.14

Authors

Broadberry, R.L.,Ott, K.L.,Lake, E.W.,Hemme, C.A.,Chi, S.,LeBeau, A.M.,Grant, T. (deposition date: 2026-08-06, release date: 2026-11-04)

Primary citation

Broadberry, R.L.,Ott, K.L.,Lake, E.W.,Ravi, T.,Hemme, C.A.,Chi, S.,West, J.L.,Gunaratne, G.S.,Ong, I.M.,LeBeau, A.M.,Grant, T.
A shark variable new antigen receptor recognizes an occluded epitope of fibroblast activation protein.
Biorxiv, 2026

PubMed Abstract: Variable new antigen receptors (VNARs) are the smallest naturally occurring antibody binding domains. Their size allows VNARs to access sterically restricted epitopes that are inaccessible to conventional antibodies. We recently identified a suite of VNARs that target fibroblast activation protein (FAP), a stromal serine protease indicative of extracellular matrix remodeling. The presence of FAP on the surface of cancer-associated fibroblasts (CAFs) that promote immunosuppression has made FAP a compelling therapeutic target for cancer therapy. Although antibodies targeting FAP have been developed, there is a paucity of information on how biologics engage FAP. Here, we used single-particle cryogenic electron microscopy (cryo-EM) to compare FAP recognition of three antibody architectures: a shark-derived VNAR, variable heavy (V) and light domains (V) of a humanized Immunoglobulin G (IgG), and a camelid-derived VHH. The humanized V-V domains and camelid VHH both target a solvent-exposed β-propeller domain, whereas the VNAR binds a highly conserved, topologically recessed epitope at the FAP dimer interface. Radical-footprinting mass spectrometry (MS) further mapped two additional immune-derived VNARs to distinct FAP surfaces outside the shared β-propeller epitope. These findings demonstrate how unique VNAR architecture can expand access to underexplored FAP surfaces and establish a structural framework for rational multiepitope targeting strategies.

PubMed: 42845595
DOI: 10.64898/2026.08.11.744296

Experimental method

ELECTRON MICROSCOPY (2.5 Å)