1RMZ

Crystal structure of the catalytic domain of human MMP12 complexed with the inhibitor NNGH at 1.3 A resolution

Summary for 1RMZ

• Entry DOI: 10.2210/pdb1rmz/pdb
• Related: 1JK3 1OS2 1OS9
• Descriptor: Macrophage metalloelastase, ZINC ION, CALCIUM ION, ... (5 entities in total)
• Functional Keywords: matrix metalloproteinase, mmp12, elastase, complex (elastase-inhibitor), metallo elastase, nngh, hydrolase
• Biological source: Homo sapiens (human)
• Cellular location: Secreted, extracellular space, extracellular matrix (Probable): P39900
• Total number of polymer chains: 1
• Total formula weight: 18183.09

Authors

Bertini, I.,Calderone, V.,Fragai, M.,Luchinat, C.,Mangani, S.,Terni, B. (deposition date: 2003-11-28, release date: 2004-12-14, Last modification date: 2023-08-23)

Primary citation

Bertini, I.,Calderone, V.,Cosenza, M.,Fragai, M.,Lee, Y.M.,Luchinat, C.,Mangani, S.,Terni, B.,Turano, P.
Conformational variability of matrix metalloproteinases: beyond a single 3D structure.
Proc.Natl.Acad.Sci.Usa, 102:5334-5339, 2005

PubMed Abstract: The structures of the catalytic domain of matrix metalloproteinase 12 in the presence of acetohydroxamic acid and N-isobutyl-N-[4-methoxyphenylsulfonyl]glycyl hydroxamic acid have been solved by x-ray diffraction in the crystalline state at 1.0 and 1.3-A resolution, respectively, and compared with the previously published x-ray structure at 1.2-A resolution of the adduct with batimastat. The structure of the N-isobutyl-N-[4-methoxyphenylsulfonyl]glycyl hydroxamic acid adduct has been solved by NMR in solution. The three x-ray structures and the solution structure are similar but not identical to one another, the differences being sizably higher in the loops. We propose that many of the loops show a dynamical behavior in solution on a variety of time scales. Different conformations of some flexible regions of the protein can be observed as "frozen" in different crystalline environments. The mobility in solution studied by NMR reveals conformational equilibria in accessible time scales, i.e., from 10(-5) s to ms and more. Averaging of some residual dipolar couplings is consistent with further motions down to 10(-9) s. Finally, local thermal motions of each frozen conformation in the crystalline state at 100 K correlate well with local motions on the picosecond time scale. Flexibility/conformational heterogeneity in crucial parts of the catalytic domain is a rule rather than an exception in matrix metalloproteinases, and its extent may be underestimated by inspection of one x-ray structure. Backbone flexibility may play a role in the difficulties encountered in the design of selective inhibitors, whereas it may be a requisite for substrate binding and broad substrate specificity.

PubMed: 15809432
DOI: 10.1073/pnas.0407106102

Experimental method

X-RAY DIFFRACTION (1.34 Å)