Dependence of High Affinity of Metalloprotease for Inhibitor on Internal Millisecond Motions
EMSL Project ID
25597
Abstract
Matrix metalloproteinases (MMPs), and tissue inhibitors of metalloproteinases (TIMPs) that inhibit them, control the healthy tissue remodeling of wound healing, development in children, and reproductive events in women. MMPs and TIMPs also control the pathological tissue remodeling in inflammatory diseases such as cancer, arthritis and key diseases of arteries, lungs, kidneys, intestines and gums. The basic physical chemistry of how TIMPs achieve high affinity for MMPs is intriguing but inadequately understood. We reported surprising features of the association. The high affinity of a typical TIMP and MMP is endothermic. Included in the large entropy gain driving the tight binding is the conformational entropy gain from the core of TIMP-1, far from the interface, being mobilized by binding of MMP-3. These behaviors may generalize to the TIMP-MMP interactions with some of the other 25 MMPs known in humans, as well as those in animals and other species. We request 800 MHz NMR time with cryogenic probe at EMSL, and possibly 900 or 750 MHz time. This will amplify the line broadening from the conformational exchange within N-TIMP-1 bound to MMP-3, a 35 kDa complex. We will detect and quantify the line broadening as relaxation dispersions of both the backbone and side chain methyl groups. We seek to describe the rates, thermodynamics and correlated network of millisecond motions within TIMP-1 induced by MMP-3. We hope to discover the correlated network of motion that couples the interface and MMP-binding ridge of TIMP-1 to the core of TIMP-1. Detailed understanding of MMP-3 interaction with TIMP-1 may prove to be both representative and predictive of the mechanisms of associations in this key class of proteases and inhibitors.
Project Details
Project type
Large-Scale EMSL Research
Start Date
2007-05-23
End Date
2009-09-30
Status
Closed
Released Data Link
Team
Principal Investigator