7pgm | pdb_00007pgm

HHIP-C in complex with heparin

spinqualitylabelsall models 7pgm, resolution 2.70Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7pgm is a 3 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: IDS, SGN Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [HHIP_HUMAN] Modulates hedgehog signaling in several cell types including brain and lung through direct interaction with members of the hedgehog family. Publication Abstract from PubMed Hedgehog (HH) morphogen signalling, crucial for cell growth and tissue patterning in animals, is initiated by the binding of dually lipidated HH ligands to cell surface receptors. Hedgehog-Interacting Protein (HHIP), the only reported secreted inhibitor of Sonic Hedgehog (SHH) signalling, binds directly to SHH with high nanomolar affinity, sequestering SHH. Here, we report the structure of the HHIP N-terminal domain (HHIP-N) in complex with a glycosaminoglycan (GAG). HHIP-N displays a unique bipartite fold with a GAG-binding domain alongside a Cysteine Rich Domain (CRD). We show that HHIP-N is required to convey full HHIP inhibitory function, likely by interacting with the cholesterol moiety covalently linked to HH ligands, thereby preventing this SHH-attached cholesterol from binding to the HH receptor Patched (PTCH1). We also present the structure of the HHIP C-terminal domain in complex with the GAG heparin. Heparin can bind to both HHIP-N and HHIP-C, thereby inducing clustering at the cell surface and generating a high-avidity platform for SHH sequestration and inhibition. Our data suggest a multimodal mechanism, in which HHIP can bind two specific sites on the SHH morphogen, alongside multiple GAG interactions, to inhibit SHH signalling. Hedgehog-Interacting Protein is a multimodal antagonist of Hedgehog signalling.,Griffiths SC, Schwab RA, El Omari K, Bishop B, Iverson EJ, Malinauskas T, Dubey R, Qian M, Covey DF, Gilbert RJC, Rohatgi R, Siebold C Nat Commun. 2021 Dec 9;12(1):7171. doi: 10.1038/s41467-021-27475-2. PMID:34887403 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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