6HV2

MMP-13 in complex with the peptide IMISF

Summary for 6HV2

• Entry DOI: 10.2210/pdb6hv2/pdb
• Descriptor: Collagenase 3, ZINC ION, CALCIUM ION, ... (6 entities in total)
• Functional Keywords: peptidase, matrix metallo protease, self-degradation, mmp, metal binding protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 19862.00

Authors

Mittl, P.,Riedl, R.,Hohl, D. (deposition date: 2018-10-10, release date: 2019-01-30, Last modification date: 2024-01-24)

Primary citation

Gall, F.M.,Hohl, D.,Frasson, D.,Wermelinger, T.,Mittl, P.R.E.,Sievers, M.,Riedl, R.
Drug Design Inspired by Nature: Crystallographic Detection of an Auto-Tailored Protease Inhibitor Template.
Angew.Chem.Int.Ed.Engl., 58:4051-4055, 2019

PubMed Abstract: 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, which was auto-tailored by the therapeutic target MMP-13 through partial self-degradation and subsequent structure-based optimization to a highly potent and selective β-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 IC of 21 nm for MMP-13 and an attractive selectivity profile with respect to a polypharmacology approach including the anticancer targets MMP-2 (IC : 170 nm) and MMP-9 (IC : 140 nm).

PubMed: 30615822
DOI: 10.1002/anie.201812348

Experimental method

X-RAY DIFFRACTION (1.709 Å)