6hv2 | pdb_00006hv2

MMP-13 in complex with the peptide IMISF

spinqualitylabelsall models 6hv2, resolution 1.71Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6hv2 is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.709Å Ligands: CA, GOL, ZN Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease MMP13_HUMAN Defects in MMP13 are the cause of spondyloepimetaphyseal dysplasia Missouri type (SEMD-MO) [MIM:602111. A bone disease characterized by moderate to severe metaphyseal changes, mild epiphyseal involvement, rhizomelic shortening of the lower limbs with bowing of the femora and/or tibiae, coxa vara, genu varum and pear-shaped vertebrae in childhood. Epimetaphyseal changes improve with age. Defects in MMP13 are the cause of metaphyseal anadysplasia type 1 (MANDP1) [MIM:602111. Metaphyseal anadysplasia consists of an abnormal bone development characterized by severe skeletal changes that, in contrast with the progressive course of most other skeletal dysplasias, resolve spontaneously with age. Clinical characteristics are evident from the first months of life and include slight shortness of stature and a mild varus deformity of the legs. Patients attain a normal stature in adolescence and show improvement or complete resolution of varus deformity of the legs and rhizomelic micromelia. Function MMP13_HUMAN Degrades collagen type I. Does not act on gelatin or casein. Could have a role in tumoral process. Publication Abstract from PubMed De novo drug discovery is still a challenge in the search for potent and selective modulators of therapeutically relevant target proteins. Here, we disclose the unexpected discovery of a peptidic ligand 1 by X-ray crystallography, auto-tailored by the therapeutic target MMP-13 through partial self-degradation and the subsequent structure-based optimization to a highly potent and selective beta-sheet peptidomimetic inhibitor derived from the endogenous tissue inhibitors of metalloproteinases (TIMPs). The incorporation of non-proteinogenic amino acids in combination with a cyclization strategy proved to be key for the de novo design of TIMP peptidomimetics. The optimized cyclic peptide 4 (ZHAWOC7726) is membrane permeable with an IC50 of 21 nM for MMP-13 and an attractive selectivity profile with respect to a polypharmacology approach including the anti-cancer targets MMP-2 (IC50: 170 nM) and MMP-9 (IC50: 140 nM). Drug design inspired by Nature: Crystallographic detection of auto-tailored protease inhibitor template.,Gall FM, Hohl D, Frasson D, Wermelinger T, Mittl PRE, Sievers M, Riedl R Angew Chem Int Ed Engl. 2019 Jan 7. doi: 10.1002/anie.201812348. PMID:30615822 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Matrix metalloproteinase 3D structures

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