3MA2

Complex membrane type-1 matrix metalloproteinase (MT1-MMP) with tissue inhibitor of metalloproteinase-1 (TIMP-1)

Summary for 3MA2

• Entry DOI: 10.2210/pdb3ma2/pdb
• Related: 1BQQ
• Descriptor: Matrix metalloproteinase-14, Metalloproteinase inhibitor 1, CALCIUM ION, ... (5 entities in total)
• Functional Keywords: protein - protein complex, cleavage on pair of basic residues, disulfide bond, membrane, metal-binding, metalloprotease, protease, transmembrane, zymogen, erythrocyte maturation, glycoprotein, metalloenzyme inhibitor, metalloprotease inhibitor, secreted, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (human); More
• Cellular location: Membrane ; Single-pass type I membrane protein : P50281; Secreted : P01033
• Total number of polymer chains: 4
• Total formula weight: 69797.72

Authors

Grossman, M.,Tworowski, D.,Dym, O.,Lee, M.-H.,Levy, Y.,Sagi, I. (deposition date: 2010-03-23, release date: 2010-06-30, Last modification date: 2024-11-06)

Primary citation

Grossman, M.,Tworowski, D.,Dym, O.,Lee, M.H.,Levy, Y.,Murphy, G.,Sagi, I.
The Intrinsic Protein Flexibility of Endogenous Protease Inhibitor TIMP-1 Controls Its Binding Interface and Affects Its Function.
Biochemistry, 49:6184-6192, 2010

PubMed Abstract: Protein flexibility is thought to play key roles in numerous biological processes, including antibody affinity maturation, signal transduction, and enzyme catalysis, yet only limited information is available regarding the molecular details linking protein dynamics with function. A single point mutation at the distal site of the endogenous tissue inhibitor of metalloproteinase 1 (TIMP-1) enables this clinical target protein to tightly bind and inhibit membrane type 1 matrix metalloproteinase (MT1-MMP) by increasing only the association constant. The high-resolution X-ray structure of this complex determined at 2 A could not explain the mechanism of enhanced binding and pointed to a role for protein conformational dynamics. Molecular dynamics (MD) simulations reveal that the high-affinity TIMP-1 mutants exhibit significantly reduced binding interface flexibility and more stable hydrogen bond networks. This was accompanied by a redistribution of the ensemble of substrates to favorable binding conformations that fit the enzyme catalytic site. Apparently, the decrease in backbone flexibility led to a lower entropy cost upon formation of the complex. This work quantifies the effect of a single point mutation on the protein conformational dynamics and function of TIMP-1. Here we argue that controlling the intrinsic protein dynamics of MMP endogenous inhibitors may be utilized for rationalizing the design of selective novel protein inhibitors for this class of enzymes.

PubMed: 20545310
DOI: 10.1021/bi902141x

Experimental method

X-RAY DIFFRACTION (2.05 Å)