3ma2

Publication Abstract from PubMed

Protein flexibility is thought to play key roles during 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 2A 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 redistribution of the ensemble of substrates to favorable binding conformations that fit the enzyme catalytic site. Apparently, the decrease in backbone flexibility lead to lower entropy cost upon complex formation. This work quantifies the effect of a single point mutation on protein conformational dynamics and function of TIMP-1. Here we argue that controlling intrinsic protein dynamics of MMPs endogenous inhibitors may be utilized for rationalizing the design of selective novel protein inhibitors for this class of enzymes.

Intrinsic protein flexibility of endogenous protease inhibitor TIMP-1 controls its binding interface and effects its function.,Grossman M, Tworowski D, Dym O, Lee MH, Levy Y, Murphy G, Sagi I Biochemistry. 2010 Jun 14. PMID:20545310^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.