2012
DOI: 10.1074/jbc.m112.341156
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Matrix Metalloproteinase-10 (MMP-10) Interaction with Tissue Inhibitors of Metalloproteinases TIMP-1 and TIMP-2

Abstract: Background: Stromelysins MMP-3 and MMP-10 serve distinct functions, and differential inhibition by TIMPs offers one mechanism of control.Results: MMP-10 shows reduced sensitivity to TIMP-1 and -2; the MMP-10⅐TIMP-1 structure provides insights into inhibitor specificity. Conclusion: MMP sequence homology poorly predicts TIMP affinity, where subtle conformational differences shape selectivity. Significance: Our results clarify biological protease regulation and suggest strategies for engineering TIMP selectivity. Show more

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Cited by 100 publications
(118 citation statements)
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References 86 publications
(74 reference statements)
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“…43 Also, while TIMP-1 and TIMP-2 bind MMP-10 (stromelysin-2), the binding is 10-fold weaker than that to MMP-3 (stromelysin-1). 44 TIMP-1 has a threonine-2 (Thr2) residue that interacts with the MMP S1’ pocket in a manner similar to that of a substrate P1’ substituent, largely determining the affinity to MMP-3. Substitutions at Thr2 affect the stability of the TIMP-MMP complex and the TIMP specificity to different MMPs.…”
Section: Tissue Inhibitors Of Metalloproteinases (Timps)mentioning
confidence: 99%
“…43 Also, while TIMP-1 and TIMP-2 bind MMP-10 (stromelysin-2), the binding is 10-fold weaker than that to MMP-3 (stromelysin-1). 44 TIMP-1 has a threonine-2 (Thr2) residue that interacts with the MMP S1’ pocket in a manner similar to that of a substrate P1’ substituent, largely determining the affinity to MMP-3. Substitutions at Thr2 affect the stability of the TIMP-MMP complex and the TIMP specificity to different MMPs.…”
Section: Tissue Inhibitors Of Metalloproteinases (Timps)mentioning
confidence: 99%
“…For example, whereas TIMP-2 and -3 can inhibit MT1-MMP and MT2-MMP, TIMP-1 is a poor inhibitor of MT1-MMP, MT3-MMP, MT5-MMP, and MMP-19 (Baker et al, 2002). Also, the binding of TIMP-1 and -2 to MMP-10 (stromelysin-2) is 10-fold weaker than their binding to MMP-3 (stromelysin-1) (Batra et al, 2012). TIMP-1 has a Thr2 residue that interacts with the specific P19 substituent of MMP-3, and substitutions at Thr2 affect the stability of the TIMP-MMP complex and the specificity for different MMPs.…”
Section: Timps and Timp/mmp Ratiomentioning
confidence: 99%
“…109 Also, while TIMP-1 and -2 can bind MMP-10 (stromelysin-2), their binding is 10-fold weaker than that to MMP-3 (stromelysin-1). 110 Importantly, TIMP-1 has a threonine-2 (Thr2) side chain that enters the MMP S1′ pocket in a manner similar to that of a substrate P1′ substituent, largely determining the affinity to MMP-3. Substitutions at Thr2 could affect the stability of the TIMP-MMP complex and the TIMP specificity for different MMPs.…”
Section: Potential Benefits Of Mmp Inhibitors In Vvsmentioning
confidence: 99%