Constraining specificity in the N‐domain of tissue inhibitor of metalloproteinases‐1; gelatinase‐selective inhibitors

Hamze, Asmaa B.; Wei, Shuo; Bahudhanapati, Harinath; Kota, Smitha; Acharya, K. Ravi; Brew, Keith

doi:10.1110/ps.072978507

Cited by 63 publications

(77 citation statements)

References 42 publications

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“…Interactions in this region have proven critical in modulating TIMP selectivity toward other MMPs. For example, replacement of the TIMP-1 AB loop with the much longer TIMP-2 AB loop has minimal impact on affinity toward MMP-1, which makes no natural contacts with the TIMP-1 AB loop, but substantially weakens affinity toward MMP-3cd, presumably by disrupting the favorable contacts with the N terminus of MMP-3cd (84). We speculate that optimization of the length and sequence of the TIMP AB loop to disrupt MMP-3 interactions while favoring MMP-10 interactions may be one useful step toward the development of MMP-10-selective TIMPs.…”

Section: Discussionmentioning

confidence: 99%

Matrix Metalloproteinase-10 (MMP-10) Interaction with Tissue Inhibitors of Metalloproteinases TIMP-1 and TIMP-2

Batra

Robinson

Soares

et al. 2012

Journal of Biological Chemistry

100

105

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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.

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Section: Discussionmentioning

confidence: 99%

Matrix Metalloproteinase-10 (MMP-10) Interaction with Tissue Inhibitors of Metalloproteinases TIMP-1 and TIMP-2

Batra

Robinson

Soares

et al. 2012

Journal of Biological Chemistry

100

105

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“…The association constant of TIMP-1 with the MT1-MMP enzyme, however, is exceedingly poor. This association constant is significantly less efficient compared with those of TIMP-2 and TIMP-3 (23,24). As a result, TIMP-1 is not capable of inhibiting the cellular MT1-MMP activity, especially under a physiological range of inhibitor concentrations and especially if compared with TIMP-2 (8, 21).…”

Section: Timp⅐mmp Inhibitorymentioning

confidence: 98%

“…The Cys 1 coordinates, via bidentate interactions, the catalytic zinc of the MMP active site. Normally, TIMPs perform as nanomolar or even femtomolar range inhibitors of MMPs (8,[19][20][21][22].Multiple studies have been performed to constrain the specificity of TIMPs and transform TIMPs into selective rather than wide-ranging inhibitors (14,(23)(24)(25)(26). The inhibitory NT-TIMP alone and the individual CAT of MMPs were predominantly used in these studies.…”

mentioning

confidence: 99%

“…Multiple studies have been performed to constrain the specificity of TIMPs and transform TIMPs into selective rather than wide-ranging inhibitors (14,(23)(24)(25)(26). The inhibitory NT-TIMP alone and the individual CAT of MMPs were predominantly used in these studies.…”

mentioning

confidence: 99%

“…Differences in contacts and chemistry of the interfaces of TIMP⅐MMP complexes provide a basis for re-engineering of the inhibitory selectivity. Because of its exceedingly poor association constant, TIMP-1 is incapable of efficiently inhibiting the full-length MT1-MMP enzyme, albeit a certain level of inhibition was observed with the individual catalytic domain of MT1-MMP (21,23,24). A single point mutation of Thr 98 to Leu (T98L) at a distal site from the inhibitory loop, however, increased the association constant and transformed the NT-TIMP of TIMP-1 into a tight-binding inhibitor of MT1-MMP (14,27).…”

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confidence: 99%

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Dynamic Interdomain Interactions Contribute to the Inhibition of Matrix Metalloproteinases by Tissue Inhibitors of Metalloproteinases

Remacle

Shiryaev

Radichev

et al. 2011

Journal of Biological Chemistry

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Because of their important function, matrix metalloproteinases (MMPs) are promising drug targets in multiple diseases, including malignancies. The structure of MMPs includes a catalytic domain, a hinge, and a hemopexin domain (PEX), which are followed by a transmembrane and cytoplasmic tail domains or by a glycosylphosphatidylinositol linker in membrane-type MMPs (MT-MMPs). TIMPs-1, -2, -3, and -4 are potent natural regulators of the MMP activity. These are the inhibitory N-terminal and the non-inhibitory C-terminal structural domains in TIMPs. Based on our structural modeling, we hypothesized that steric clashes exist between the non-inhibitory C-terminal domain of TIMPs and the PEX of MMPs. Conversely, a certain mobility of the PEX relative to the catalytic domain is required to avoid these obstacles. Because of its exceedingly poor association constant and, in contrast with TIMP-2, TIMP-1 is inefficient against MT1-MMP. We specifically selected an MT1-MMP⅐TIMP-1 pair to test our hypothesis, because any improvement of the inhibitory potency would be readily recorded. We characterized the domain-swapped MT1-MMP chimeras in which the PEX of MMP-2 (that forms a complex with TIMP-2) and of MMP-9 (that forms a complex with TIMP-1) replaced the original PEX in the MT1-MMP structure. In contrast with the wild-type MT1-MMP, the diverse proteolytic activities of the swapped-PEX chimeras were then inhibited by both TIMP-1 and TIMP-2. Overall, our studies suggest that the structural parameters of both domains of TIMPs have to be taken into account for their re-engineering to harness the therapeutic in vivo potential of the novel TIMP-based MMP antagonists with constrained selectivity.There are 24 individual MMPs 2 in humans. MMPs cleave multiple extracellular matrix components, growth factors, cytokines, and cell signaling adhesion receptors. Aberrant performance of MMPs plays a role in a plethora of diseases, including cancer (1-3). There are 18 soluble and 6 membrane MMPs. The structure of soluble MMPs includes a prodomain (PRO), a catalytic domain (CAT) that contains the active site zinc, a hinge, and a PEX. Additionally, membrane-type MMPs (MT-MMP) contain a transmembrane domain followed by a short cytoplasmic tail (CYTO) (MT1-MMP, MT2-MMP, MT3-MMP, and MT5-MMP) or a glycosylphosphatidylinositol moiety (MT4-MMP and MT6-MMP) that anchors the proteinase to the cell surface (1, 4, 5).MMPs are synthesized as zymogens, which require the proteolytic processing of the N-terminal inhibitory PRO to generate the active enzymes (4). It is accepted that secretory tissue inhibitors of MMPs (TIMPs) play an important role in the regulation of the proteolytic activity of MMPs (6, 7). Four TIMPs (TIMP-1, -2, -3, and -4) are present in humans (8). There is at least a 25% sequence identity among all TIMPs, including 12 conserved Cys residues that form 6 disulfide bridges resulting in 6 loop regions. There are two domains, N-terminal and C-terminal, in TIMPs. An N-terminal domain (NT-TIMP) binds the CAT, carries the MMP-inhibitory activ...

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Matrix Metalloproteinases: An Overview

Nagase

Visse

2009

Drug Design of Zinc‐Enzyme Inhibitors

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Constraining specificity in the N‐domain of tissue inhibitor of metalloproteinases‐1; gelatinase‐selective inhibitors

Cited by 63 publications

References 42 publications

Matrix Metalloproteinase-10 (MMP-10) Interaction with Tissue Inhibitors of Metalloproteinases TIMP-1 and TIMP-2

Matrix Metalloproteinase-10 (MMP-10) Interaction with Tissue Inhibitors of Metalloproteinases TIMP-1 and TIMP-2

Dynamic Interdomain Interactions Contribute to the Inhibition of Matrix Metalloproteinases by Tissue Inhibitors of Metalloproteinases

Matrix Metalloproteinases: An Overview

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