Structure analysis reveals the flexibility of the ADAMTS‐5 active site

Abstract

A ((1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl) succinamide derivative (here referred to as Compound 12) shows significant activity toward many matrix metalloproteinases (MMPs), including MMP-2, MMP-8, MMP-9, and MMP-13. Modeling studies had predicted that this compound would not bind to ADAMTS-5 (a disintegrin and metalloproteinase with thrombospondin motifs-5) due to its shallow S1 0 pocket. However, inhibition analysis revealed it to be a nanomolar inhibitor of both ADAMTS-4 and 25. The observed inconsistency was explained by analysis of crystallographic structures, which showed that Compound 12 in complex with the catalytic domain of ADAMTS-5 (cataTS5) exhibits an unusual conformation in the S1 0 pocket of the protein. This first demonstration that cataTS5 can undergo an induced conformational change in its active site pocket by a molecule like Compound 12 should enable the design of new aggrecanase inhibitors with better potency and selectivity profiles.

Computational Insights into ADAMTS4, ADAMTS5 and MMP13 Inhibitor Selectivity

“…The main structural differences that can be explored to meet selectivity requirements for ADAMTS4 and ADAMTS5 versus others metalloproteinases involve the outward facing S2′ pocket, delimited by the S2′‐loop amino acid residues 319–323 and the inward facing S1′ pocket, delimited by the S1′‐loop amino acid residues 393–399 (Figure 1). 12,14 In particular, the size and the shape of the S1′ pocket seems to be mainly determined by four non conserved amino acids, underlined in Figure 1 c, whose bulky side‐chains reduce the cavity accessibility in different extents for the three enzymes 14,15…”

“…Significant structural differences in the conformation of the S2′ loop (Figure 1 b 1 and 1 b 2) arise mainly from: i) the presence of the C 322 C 327 sulfur bridge peculiar to the S2′ loop in ADAMTSs;12 ii) a second tightly bound zinc ion (the so‐called structural zinc) besides the catalytic zinc, only present in MMPs, and, iii) a different coordination for the Calcium ion placed in proximity of the turn of the loop in MMPs with respect to ADAMTSs 15…”

Molecular basis for the mechanism of action of an anti-TACE antibody

“…Structural alignment of M-domain structures shows that the epitope of MEDI3622, the surface loop of sIVa-sIVb β-hairpin in the TACE M-domain, is a structural feature unique to TACE. The M-domain is shown in magenta for TACE (PDB 3E8R), 16 blue for ADAMTS-5 (PDB 3LJT), 30 cyan for MMP-9 (PDB 5CUH) 31 and gray for ADAM22 (PDB 3G5C) 32 …”

Emerging roles for ADAMTS5 during development and disease

“…Independent research groups subsequently solved the crystal structure of ADAMTS5's catalytic domain (Mosyak et al, 2008;Shieh et al, 2008), to facilitate the emergence of ADAMTS5-specific small molecule inhibitors (Shieh et al, 2011). Aside from the comprehensive literature examining the role of ADAMTS5 in arthritide biology (reviewed in ), which is not discussed in detail in this current review, little is known about its function in other pathological contexts.…”